Methods and Compositions for Treating Attention Deficit Hyperactivity Disorder, Anxiety and Insomnia Using Dexmedetomidine Transdermal Compositions

ABSTRACT

Aspects of the invention include methods of treating ADHD, anxiety or insomnia by applying a transdermal delivery device containing a dexmedetomidine composition formulated to deliver an amount of dexmedetomidine to a subject diagnosed as having ADHD, anxiety or insomnia. In practicing methods according to certain embodiments, a transdermal delivery device having a dexmedetomidine composition is applied to a subject and is maintained in contact with the subject in a manner sufficient to deliver an amount of dexmedetomidine sufficient to treat ADHD, anxiety or insomnia in the subject. Also provided are transdermal delivery devices configured to deliver an amount of dexmedetomidine sufficient for practicing the subject methods, as well as kits containing the transdermal delivery devices.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/505,933 filed Oct. 3, 2014, which application, pursuant to 35 U.S.C.§ 119(e), claims priority to the filing date of U.S. ProvisionalApplication Ser. No. 61/887,862 filed Oct. 7, 2013, the disclosure ofwhich is herein incorporated by reference.

INTRODUCTION

Attention Deficit Hyperactivity Disorder (ADHD) is a neurobehavioraldisorder characterized primarily by inattention, easy distractibility,disorganization, procrastination, and forgetfulness. Attention DeficitHyperactivity Disorder is a condition that typically manifests inchildren in the preschool and early school years making it difficult forthese children to control their behavior or pay attention. It isestimated that between 3 and 5 percent of children have attentiondeficit hyperactivity disorder (ADHD), or approximately 2 millionchildren in the United States. It is believed that in a classroom of 24to 30 children, there is likely that at least one child will have ADHD.ADHD is characterized by inattention, hyperactivity, and impulsivity.The America Psychiatric Association in the Diagnostic and StatisticalManual of Mental Disorders have established three sub-types of ADHD.ADHD Predominantly Inattentive Type (ADHD-PI) presents with symptomsincluding being easily distracted, forgetful, daydreaming,disorganization, poor concentration, and difficulty completing tasks.ADHD, Predominantly Hyperactive-Impulsive Type presents with excessivefidgetiness and restlessness, hyperactivity, difficulty waiting andremaining seated, immature behavior; destructive behaviors may also bepresent. ADHD, Combined Type is a combination of ADHD PredominantlyInattentive Type and ADHD, Predominantly Hyperactive-Impulsive Type.

Anxiety disorder is a psychiatric disorder characterized by excessiverumination, worrying, uneasiness, apprehension and fear about futureuncertainties either based on real or imagined events, which may affectboth physical and psychological health. The American PsychiatricAssociation has established that term anxiety includes four aspects orexperiences that an individual with anxiety disorder may have: mentalapprehension, physical tension, physical symptoms and dissociativeanxiety.

Insomnia is a sleep disorder in which there is an inability to fallasleep or to stay asleep as long as desired. Insomnia is oftenattributed both as a sign and as a symptom of accompanying sleep,medical, and/or psychiatric disorders characterized by a persistentdifficulty falling asleep, staying asleep or suffering from sleep ofpoor quality. Insomnia is typically followed by functional impairmentwhile awake. Insomnia can occur at any age, but it is particularlycommon in the elderly. Insomnia can be persistent for a short duration(e.g., lasting less than three weeks) or for a long duration (e.g.,lasting greater than 3-4 weeks), which often leads to memory problems,depression, irritability and an increased risk of heart disease andautomobile related accidents.

Dexmedetomidine is the S-enantiomer of medetomidine and is an agonist ofα₂-adrenergic receptors that is used as a sedative medication inintensive care units and by anesthetists for intubated and nonintubatedpatients requiring sedation for surgery or short term procedures. Theα₂-adrenergic receptor is a G-protein coupled receptor associated withthe G_(i) heterotrimeric G-protein that includes three highly homologoussubtypes, including α_(2a), α_(2b) and α_(2c)-adrenergic receptors.Agonists of the a₂-adrenergic receptor are implicated in sedation,muscle relaxation and analgesia through effects on the central nervoussystem.

Dexmedetomidine is used in clinical settings as a sedative throughparenteral, intravenous and oral administration and thus, requires closesupervision by a health care professional in a hospital setting.Dexmedetomidine is currently employed for sedation of intubated ormechanically ventilated subjects in an in-clinic (e.g., hospital)setting as well as for the sedation of non-intubated subjects as a partof monitored anesthesia during surgery, radiography or diagnosticprocedures. Dexmedetomidine is also approved for continuous intravenousinfusion in non-intubated subjects since it does not adversely affectbreathing.

SUMMARY

Aspects of the invention include methods of treating ADHD, anxiety orinsomnia by applying a transdermal delivery device containing adexmedetomidine composition formulated to deliver an amount ofdexmedetomidine to a subject diagnosed as having ADHD, anxiety orinsomnia. In practicing methods according to certain embodiments, atransdermal delivery device having a dexmedetomidine composition isapplied to a subject and is maintained in contact with the subject in amanner sufficient to deliver an amount of dexmedetomidine sufficient totreat ADHD, anxiety or insomnia in the subject. Also provided aretransdermal delivery devices configured to deliver an amount ofdexmedetomidine sufficient for practicing the subject methods, as wellas kits containing the transdermal delivery devices.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows an example of a plot of average dexmedetomidine flux as afunction of transdermal delivery device application time for adexmedetomidine transdermal composition with polyisobutylene/polybuteneand crosslinked polyvinylpyrrolidone adhesive according to oneembodiment.

FIG. 2 (Panel A) shows an example of cumulative dexmedetomidinedelivered amount with time according to one embodiment. FIG. 2 (Panel B)shows an example of a plot of average dexmedetomidine flux as a functionof transdermal delivery device application time for a dexmedetomidinetransdermal composition having a non-functionalized acrylate adhesiveaccording to one embodiment. FIG. 2 (Panel C) shows an example ofdexmedetomidine utilization with time according to one embodiment.

FIG. 3 shows an example of a plot of average dexmedetomidine flux as afunction of transdermal delivery device application time for adexmedetomidine transdermal composition having a non-functionalizedacrylate adhesive according to one embodiment.

FIG. 4 shows an example of a plot of average dexmedetomidine flux as afunction of transdermal delivery device application time for adexmedetomidine transdermal composition having a hydroxyl functionalizedacrylate adhesive containing vinyl acetate according to one embodiment.

FIG. 5 shows an example of a plot of average dexmedetomidine flux as afunction of transdermal delivery device application time for adexmedetomidine transdermal composition having a hydroxyl functionalizedacrylate adhesive according to another embodiment.

FIG. 6 shows an example of a plot of average dexmedetomidine flux as afunction of transdermal delivery device application time for adexmedetomidine transdermal composition having hydroxyl functionalizedacrylate adhesive and a hydroxyl functionalized acrylate adhesivecontaining vinyl acetate according to another embodiment.

FIGS. 7A-7B shows an example of a plot of average dexmedetomidine fluxas a function of transdermal delivery device application time fordexmedetomidine transdermal compositions having a non-functionalizedacrylate adhesive, a hydroxyl functionalized acrylate adhesive and ahydroxyl functionalized acrylate adhesive containing vinylacetateaccording to one embodiment.

FIG. 8 shows an example of a plot of average dexmedetomidine flux as afunction of transdermal delivery device application time for adexmedetomidine transdermal composition having a carboxylic acidfunctionalized acrylate adhesive according to another embodiment.

FIG. 9 shows an example of a plot of average dexmedetomidine flux as afunction of transdermal delivery device application time for adexmedetomidine transdermal composition having acrylic adhesive withcarboxyl group and hydroxyl group as the functional group containingvinyl acetate according to another embodiment.

FIG. 10 shows an example of a plot of average dexmedetomidine flux as afunction of transdermal delivery device application time for adexmedetomidine transdermal composition having apolyisobutylene/polybutene adhesive with a carboxylic acidfunctionalized acrylate adhesive according to one embodiment.

FIG. 11 shows an example of a plot of average dexmedetomidine flux as afunction of transdermal delivery device application time for adexmedetomidine transdermal composition having apolyisobutylene/polybutene adhesive with the solubility enhancerlevulinic acid according to one embodiment.

FIG. 12 shows an example of a plot of average dexmedetomidine flux as afunction of transdermal delivery device application time for adexmedetomidine transdermal composition having apolyisobutylene/polybutene adhesive with the solubility enhancer lauryllactate according to one embodiment.

FIG. 13 shows an example of a plot of average dexmedetomidine flux as afunction of transdermal delivery device application time for adexmedetomidine transdermal composition having apolyisobutylene/polybutene adhesive with the solubility enhancerpropylene glycolmonolaurate according to one embodiment.

FIG. 14A shows an example of a plot of average dexmedetomidine flux as afunction of transdermal delivery device application time for adexmedetomidine transdermal composition having a hydroxyl functionalizedacrylate adhesive containing vinyl acetate with levulinic acid accordingto one embodiment.

FIG. 14B shows an example of a plot of average dexmedetomidine flux as afunction of transdermal delivery device application time for adexmedetomidine transdermal composition having a hydroxyl functionalizedacrylate adhesive containing vinyl acetate with polyvinylpyrrolidoneaccording to one embodiment.

FIG. 14C shows an example of a plot of average dexmedetomidine flux as afunction of transdermal delivery device application time for adexmedetomidine transdermal composition having a hydroxyl functionalizedacrylate adhesive containing vinyl acetate with a carboxylic acidfunctionalized acrylate adhesive according to one embodiment.

FIG. 15 shows an example of a plot of average dexmedetomidine flux as afunction of transdermal delivery device application time for adexmedetomidine transdermal composition having acrylate pressuresensitive adhesive in the absence and presence of levulinic acid, oleicacid or a carboxylic acid functionalized acrylate adhesive according toone embodiment.

FIG. 16 shows an example of a plot of average dexmedetomidine flux as afunction of transdermal delivery device application time for adexmedetomidine transdermal composition having a hydroxyl functionalizedacrylate adhesive containing vinyl acetate with a carboxylic acidfunctionalized acrylate adhesive according to another embodiment.

FIG. 17 shows an example of a plot of average dexmedetomidine flux as afunction of transdermal delivery device application time for adexmedetomidine transdermal composition having a hydroxyl functionalizedacrylate adhesive containing vinyl acetate with oleic acid or acarboxylic acid functionalized acrylate adhesive according to anotherembodiment.

FIG. 18 shows an example of a plot of average dexmedetomidine flux as afunction of transdermal delivery device application time for adexmedetomidine transdermal composition having a hydroxyl functionalizedacrylate adhesive containing vinyl acetate with solubility enhancerssuch as carboxylic acid functionalized acrylate adhesives, lauryllactate or oleic acid according to another embodiment.

FIG. 19 shows the average dexmedetomidine in-vitro skin flux withrespect to time from various formulations.

FIGS. 20 and 21 show the flux on two different skin samples from variousformulations.

DETAILED DESCRIPTION

Aspects of the invention include methods of treating ADHD, anxiety orinsomnia by applying a transdermal delivery device containing adexmedetomidine composition formulated to deliver an amount ofdexmedetomidine to a subject diagnosed as having ADHD, anxiety orinsomnia. In practicing methods according to certain embodiments, atransdermal delivery device having a dexmedetomidine composition isapplied to a subject and is maintained in contact with the subject in amanner sufficient to deliver an amount of dexmedetomidine sufficient totreat ADHD, anxiety or insomnia in the subject. Also provided aretransdermal delivery devices configured to deliver an amount ofdexmedetomidine sufficient for practicing the subject methods, as wellas kits containing the transdermal delivery devices.

Before the present invention is described in greater detail, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Certain ranges are presented herein with numerical values being precededby the term “about.” The term “about” is used herein to provide literalsupport for the exact number that it precedes, as well as a number thatis near to or approximately the number that the term precedes. Indetermining whether a number is near to or approximately a specificallyrecited number, the near or approximating unrecited number may be anumber which, in the context in which it is presented, provides thesubstantial equivalent of the specifically recited number.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, representativeillustrative methods and materials are now described.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

In further describing various embodiments of the invention, methods forapplying to a subject diagnosed as having ADHD, anxiety or insomnia atransdermal delivery device having a dexmedetomidine composition andmaintaining the transdermal delivery device in contact with the subjectin a manner sufficient to deliver an amount of dexmedetomidine to treatADHD, anxiety or insomnia in the subject are first reviewed in greaterdetail. Next, transdermal delivery devices suitable for practicing thesubject methods are described. Kits that include transdermal deliverydevices of interest are then reviewed.

Methods for Treating Attention Deficit Hyperactivity Disorder (ADHD),Anxiety or Insomnia with Dexmedetomidine Transdermal Delivery Devices

Aspects of the invention include methods of treating ADHD, anxiety orinsomnia by applying a transdermal delivery device containing adexmedetomidine composition formulated to deliver an amount ofdexmedetomidine to a subject diagnosed as having ADHD, anxiety orinsomnia. In practicing methods according to certain embodiments, atransdermal delivery device having a dexmedetomidine composition isapplied to a subject and is maintained in contact with the subject in amanner sufficient to deliver an amount of dexmedetomidine sufficient totreat ADHD, anxiety or insomnia in the subject. The term “transdermal”is used in its conventional sense to refer to the route ofadministration where an active agent (i.e., drug) is delivered acrossthe skin (e.g., topical administration) or mucous membrane for systemicdistribution. As such, transdermal dexmedetomidine compositions asdescribed herein include compositions which are delivered to the subjectthrough one or more of the subcutis, dermis and epidermis, including thestratum corneum, stratum germinativum, stratum spinosum and stratumbasale. Accordingly, extended transdermal delivery devices containing atransdermal dexmedetomidine composition may be applied at any convenientlocation, such as for example, the arms, legs, buttocks, abdomen, back,neck, scrotum, vagina, face, behind the ear, buccally as well assublingually. In describing methods of the present invention, the term“subject” is meant the person or organism to which the transdermalcomposition is applied and maintained in contact. As such, subjects ofthe invention may include but are not limited to mammals, e.g., humansand other primates, such as chimpanzees and other apes and monkeyspecies; and the like, where in certain embodiments the subject arehumans. The term subject is also meant to include a person or organismof any age, weight or other physical characteristic, where the subjectsmay be an adult, a child, an infant or a newborn. Methods for treatingADHD or an associated disorder, anxiety or insomnia according to certainembodiments includes treatment of a juvenile subject. In theseembodiments, the subject may be a child under the age of 8 years, suchas a child under the age of 5 years.

Transdermal administration of dexmedetomidine may be passive or active.By “passive” transport is meant that the dexmedetomidine composition isdelivered across the skin or mucous membrane in the absence of appliedenergy (e.g., rubbing or heat) and is primarily dependent on thepermeability of the barrier (e.g., skin or mucous membrane) and byentropy of delivery. However, transdermal administration according tocertain embodiments may also include active transport of thedexmedetomidine composition across the skin or mucous membrane. Activetransport can be any convenient protocol sufficient to transport thecomposition through the skin or mucous membrane in conjunction withapplied energy and may include, but is not limited to microneedledelivery, facilitated diffusion, electrochemically-produced gradients,iontophoretic systems, among other protocols.

As summarized above, in practicing methods according to embodiments ofthe invention a transdermal delivery device having a dexmedetomidinecomposition is applied to a subject and is maintained in contact withthe subject in a manner sufficient to deliver an amount ofdexmedetomidine to treat ADHD, anxiety or insomnia in the subject. Theterm “ADHD” refers to the psychiatric disorder or neurobehavioraldisorder characterized by significant difficulties either of inattentionor hyperactivity and impulsiveness or a combination thereof. ADHD asused herein includes the Diagnostic and Statistical Manual of MentalDisorders (DSM-V) designation of the three subtypes of the disorderwhich include being predominantly inattentive (ADHD-PI or ADHD-I),predominantly hyperactive-impulsive (ADHD-HI or ADHD-H), or the twocombined (ADHD-C). In certain embodiments, disorders associated withADHD may also be treated by the subject methods, the associateddisorders including but not limited to restless legs syndrome,oppositional defiant and conduct disorder, bipolar disorder, majordepressive disorder, anxiety disorders, obsessive compulsive disorder aswell as sleep disorders including insomnia, obstructive sleep apneasyndrome. The term “anxiety disorder” is used herein in its conventionalsense to refer to the psychiatric disorder characterized by excessiverumination, worrying, uneasiness, apprehension and fear about futureuncertainties either based on real or imagined events, which may affectboth physical and psychological health (e.g., in accordance with theAmerican Psychiatric Association establishment of anxiety which includesmental apprehension, physical tension, physical symptoms anddissociative anxiety) and may include the anxiety disorders generalizedanxiety disorder (GAD), panic disorder, phobias and separation anxietydisorder. Furthermore, the term “insomnia” is used herein in itsconventional sense to refer the disorder characterized by the inabilityto fall asleep or to stay asleep as long as desired. Insomnia mayinclude any of several several sleep, medical, and psychiatric disorderswhich is characterized by a persistent difficulty falling asleep,staying asleep or suffering from sleep of poor quality.

In embodiments of the invention, a subject is diagnosed as having one ormore of ADHD, anxiety and insomnia. A subject may be diagnosed as havingADHD, anxiety or insomnia by a qualified health care professional usingany suitable protocol, such as for example protocols set forth by theAmerican Psychiatric Association. In certain instances, ADHD, anxietyand insomnia are diagnosed according to criteria provided by theDiagnostic and Statistical Manual of Mental Disorders (e.g., DSM-V,released May 2013).

In certain instances, a subject is diagnosed as having one of the threesubtypes of ADHD designated by the Diagnostic and Statistical Manual ofMental Disorders (e.g., DSM-V, released May 2013): predominantlyinattentive (ADHD-PI or ADHD-I), predominantly hyperactive-impulsive(ADHD-HI or ADHD-H), or the two combined (ADHD-C). In certainembodiments, disorders associated with ADHD may also be diagnosed in thesubject, the associated disorders including but not limited to restlesslegs syndrome, oppositional defiant and conduct disorder, bipolardisorder, major depressive disorder, anxiety disorders, obsessivecompulsive disorder as well as sleep disorders including insomnia,obstructive sleep apnea syndrome.

In other instances, subjects are diagnosed as having insomnia accordingto the Epworth Sleepiness Scale, the Sleep Disorders Questionnaire, thePittsburgh Sleep Quality Index, the Insomnia Severity Index, the use ofsleep diary to track sleeping patterns, a polysomnogram to measureactivity during sleep, actigraphy for assess sleep-wake patterns, amongother convenient protocols for diagnosing insomnia.

In yet other instances, a subject is diagnosed as having anxietyaccording to the Diagnostic and Statistical Manual of Mental Disorders(e.g., DSM-V, released May 2013) such as according to diagnosis criteriafor evaluating generalized anxiety disorder, panic disorder,post-traumatic stress disorder, obsessive compulsive disorder andseparation anxiety disorder in children.

In some embodiments, methods further include diagnosing a subject ashaving one or more of ADHD, anxiety and insomnia. In certain instances,diagnosing ADHD, anxiety and insomnia may include conducting a medicalexamination such as to rule out other causes of observable symptoms. Forexample, diagnosing ADHD may include gathering information from thesubject such through an interview, questionnaire or by review ofprevious medical conditions, diaries of sleep, nighttime activity,family history and behavioral records. This may include gatheringinformation may include observing symptoms of inattention in thesubject, hyperactivity, impulsivity or restlessness.

Diagnosing insomnia may include medical examination, interview,questionnaire and sleep tests according to the Epworth Sleepiness Scale,the Sleep Disorders Questionnaire, the Pittsburgh Sleep Quality Index,the Insomnia Severity Index as well as the use of sleep diary to tracksleeping patterns, a polysomnogram to measure activity during sleep,actigraphy for assess sleep-wake patterns, among other convenientprotocols for diagnosing insomnia.

Diagnosing anxiety may include gathering information from the subjectsuch through an interview, questionnaire or by review of previousmedical conditions, family history and behavioral records. In theseembodiments, a subject diagnosed as having anxiety may be furtherevaluate to determine if the subject has one or more of generalizedanxiety disorder, panic disorder, post-traumatic stress disorder orobsessive compulsive disorder. Where the subject is a child, diagnosingmay include determining that the subject has separation anxietydisorder.

As discussed above, methods include applying to a skin surface of asubject diagnosed as having ADHD, anxiety or insomnia a transdermaldelivery device having a dexmedetomidine composition that containsdexmedetomidine and a pressure sensitive adhesive and maintaining thetransdermal delivery device in contact with the subject in a mannersufficient to deliver dexmedetomidine over a period of time to treatADHD, anxiety or insomnia in the subject. By “treating” or “treatment”is meant at least a suppression or amelioration of the symptomsassociated with the condition affecting the subject, where suppressionand amelioration are used in a broad sense to refer to at least areduction in the magnitude of a parameter, e.g., symptom, associatedwith ADHD, anxiety or insomnia. As such, treatment of ADHD, anxiety orinsomnia includes situations where ADHD, anxiety or insomnia iscompletely inhibited, e.g., prevented from happening, or stopped, e.g.,terminated, such that the subject no longer experiences ADHD, anxiety orinsomnia.

In embodiments of the invention, methods include applying a transdermaldelivery device having a dexmedetomidine composition to a subject andmaintaining the transdermal delivery device in contact with the subjectin a manner to deliver an amount of dexmedetomidine sufficient to treatADHD, anxiety or insomnia in the subject. In certain embodiments,methods include maintaining the transdermal delivery device in contactwith the subject in a manner sufficient to deliver a sedative amount ofdexmedetomidine. By “sedative” is meant that the dexmedetomidinecomposition is formulated to deliver an amount of dexmedetomidine to thesubject which causes at least partial sedation. For example, in someinstances methods include delivering an amount of dexmedetomidine to thesubject such that the subject is characterized as being in a state wherethe subject can exhibit brisk response to light glabellar tap or loudauditory stimulus. In other instances, methods include delivering anamount of dexmedetomidine to the subject such that the subject ischaracterized as being in a state where the subject exhibits a sluggishresponse to light glabellar tap or loud auditory stimulus. In certaininstances, dexmedetomidine compositions of interest are formulated todeliver an amount of dexmedetomidine which is fully sedative and thesubject is characterized as being in a state where the subject exhibitsno response to touch or auditory stimulus.

Suitable protocols for determining level of sedation may include but arenot limited to the Ramsay Sedation Scale, the Vancouver SedativeRecovery Scale, the Glasgow Coma Scale modified by Cook and Palma, theComfort Scale, the New Sheffield Sedation Scale, the Sedation-AgitationScale, and the Motor Activity Assessment Scale, among other convenientprotocols for determining the level of sedation.

In some embodiments, methods may further include evaluating the level ofsedation of the subject to determine whether any reduction inresponsiveness or cognitive or motor activity has resulted fromadministration of a transdermal delivery device. The level of sedationmay be evaluated by any convenient protocol, such as with thosementioned above. In certain embodiments, the level of sedation isevaluated using the Ramsey Sedation Scale, (as disclosed in Ramsay, etal. Controlled sedation with alphaxalone-alphadolone, British MedJournal1974; 2:656-659, the disclosure of which is herein incorporatedby reference). For example, each subject may be evaluated by a qualifiedhealth care professional and assigned a score for the level of sedationaccording to the Ramsey Sedation Scale, summarized below.

Ramsay Sedation Scale

Score Description of Responsiveness, Cognitive and Motor Activity 1Patient is anxious and agitated or restless, or both 2 Patient isco-operative, oriented, and tranquil 3 Patient responds to commands only4 Patient exhibits brisk response to light glabellar tap or loudauditory stimulus 5 Patient exhibits a sluggish response to lightglabellar tap or loud auditory stimulus 6 Patient exhibits no response

In some embodiments, during administration of subject dexmedetomidinetransdermal compositions the level of sedation of a subject is evaluatedand the subject is assigned a Ramsey score of 2 or higher, such as 3 orhigher, such as 4 or higher and including a Ramsey score of 5. Forexample, methods may include delivering an amount of dexmedetomidine tothe subject in manner sufficient to maintain a Ramsay score of between 2and 5 in the subject, such as between 3 and 5 and including a Ramsayscore of between 4 and 5.

In certain instances, throughout administration of the dexmedetomidinetransdermal composition, the subject exhibits brisk response to lightglabellar tap or loud auditory stimulus. In other instances, throughoutadministration of the dexmedetomidine transdermal composition, thesubject exhibits a sluggish response to light glabellar tap or loudauditory stimulus. In yet other instances, throughout administration ofthe dexmedetomidine transdermal composition, the subject is fullysedated and exhibits no response to touch or auditory stimulus.

The level of sedation of a subject may be evaluated at any time duringthe methods. In some instances, the level of sedation is evaluated whilemaintaining the extended transdermal delivery device in contact with thesubject at regular intervals, e.g., every 0.25 hours, every 0.5 hours,every 1 hour, every 2 hours, every 4 hours or some other interval. Forinstance, the level of sedation may be evaluated while maintaining thetransdermal delivery device in contact with the subject, such as 15minutes after applying the transdermal delivery device to the subject,30 minutes after applying the transdermal delivery device, 1 hour afterapplying the transdermal delivery device, 2 hours after applying thetransdermal delivery device, 4 hours after applying the transdermaldelivery device including 8 hours after applying the transdermaldelivery device.

The level of sedation of the subject may be evaluated one or more timesduring a dosage interval, such as 2 or more times, such as 3 or moretimes, including 5 or more times before, during or after a dosageinterval. An upper limit for the number of times the subject may beevaluated during a dosage interval is, in some instances, 10 times orfewer, such as 7 times or fewer, such as 5 times or fewer, such as 3times or fewer and including 2 times or fewer. In certain embodiments,the number of times the subject may be evaluated during a dosageinterval ranges such as from 2 times to 10 times, such as from 3 timesto 9 times, such as from 4 times to 8 times and including from 5 timesto 7 times.

In certain embodiments, sedation level may be monitored throughout theentire time the transdermal delivery device is maintained in contactwith the subject, such by heart rate monitors, breathing monitors or byvisual observation, including with the aid of a video monitor.

Depending on the specific protocol employed, treatment of ADHD, anxietyor insomnia according to embodiments of the invention may include one ormore dosage intervals. Dosage intervals may last about 2 hours orlonger, such as 3 hours or longer, such as 4 hours or longer, such as 6hours or longer, such as 8 hours or longer, such as 12 hours or longerand including 16 hours or longer. Upper limits for dosage intervals are,in some instances 24 hours or shorter, such as 16 hours or shorter, suchas 12 hours or shorter, such as 8 hours or shorter and including 4 hoursor shorter. In certain embodiments, dosage intervals range from 4 hoursto 24 hours, such as from 6 hours to 24 hours, such as from 8 hours to14 hours and including from 12 hours to 16 hours.

In certain embodiments, dosage intervals may be overnight dosageintervals where the dosage interval begins prior to when the subjectsleeps and concludes with the waking of the subject. Depending on thephysiology and age of the subject and the desired therapeutic effect,the duration of dosage intervals and treatment protocols may vary, asdescribed in greater detail below. In some embodiments, at the beginningof the dosage interval the subject being treated is in a non-sedatedstate and is awake, alert, oriented, coherent and capable of respondingto oral or written commands including questions or requests. Delivery ofdexmedetomidine to the subject according to certain methods results inthe partial or fully sedation of the subject.

In some embodiments, sustained release transdermal administration of thedexmedetomidine composition includes multi-day delivery of atherapeutically effective amount of the dexmedetomidine active agentthat is applied to the skin of a subject. By multi-day delivery is meantthat the transdermal composition is formulated to provide atherapeutically effective amount to a subject when the transdermaldelivery device is applied to the skin of a subject for a period of timethat is 1 day or longer, such as 2 days or longer, such as 4 days orlonger, such as 7 days or longer, such as 14 days and including 30 daysor longer. In certain embodiments, transdermal delivery devices providea therapeutically effective amount of dexmedetomidine to a subject for aperiod of 10 days or longer. For multi-day delivery, an upper limitperiod of time is, in some instances, 30 days or shorter, such as 28days or shorter, such as 21 days or shorter, such as 14 days or shorter,such as 7 days or shorter and including 3 days or shorter. In certainembodiments, multi-day transdermal delivery ranges such as from 2 daysto 30 days, such as from 3 days to 28 days, such as from 4 days to 21days, such as from 5 days to 14 days and including from 6 days to 10days.

The term “treatment protocol” as used herein refers to one or moresequential dosage intervals sufficient to produce the desiredtherapeutic effect of transdermal dexmedetomidine composition. Incertain embodiments, protocols may include multiple dosage intervals. By“multiple dosage intervals” is meant more than one transdermal deliverydevice is applied and maintained in contact with the subject in asequential manner. As such, a transdermal delivery device is removedfrom contact with the subject and a new transdermal delivery device isreapplied to the subject. In practicing methods of the invention,treatment regimens may include two or more dosage intervals, such asthree or more dosage intervals, such as four or more dosage intervals,such as five or more dosage intervals, including ten or more dosageintervals.

The duration between dosage intervals in a multiple dosage intervaltreatment protocol may vary, depending on the physiology of the subjector by the treatment protocol as determined by a health careprofessional. For example, the duration between dosage intervals in amultiple dosage treatment protocol may be predetermined and follow atregular intervals. As such, the time between dosage intervals may varyand may be 1 day or longer, such as 2 days or longer, such as 3 days orlonger, such as 4 days or longer, such as 5 days or longer, such as 6days or longer, such as 7 days or longer, such as 10 days or longer,including 30 days or longer. An upper limit period of time betweendosage intervals is, in some instances, 30 days or shorter, such as 28days or shorter, such as 21 days or shorter, such as 14 days or shorter,such as 7 days or shorter and including 3 days or shorter. In certainembodiments, the time between dosage intervals ranges such as from 2days to 30 days, such as from 3 days to 28 days, such as from 4 days to21 days, such as from 5 days to 14 days and including from 6 days to 10days.

In certain instances, the duration between dosage intervals may dependon the plasma concentration of dexmedetomidine during the time thetransdermal delivery device is not in contact with the subject betweendosage intervals. For example, a subsequent dosage interval may commencewhen the plasma concentration of dexmedetomidine reaches below aparticular threshold.

Methods for treating ADHD, anxiety and insomnia in a subject accordingto some embodiments may include applying a transdermal delivery devicecontaining a dexmedetomidine composition and maintaining the transdermaldelivery device in contact with the subject in a manner sufficient todeliver dexmedetomidine to a subject at a rate which averages from 1μg/hour to 10 μg/hour over the course of the dosage interval (e.g., a 8hour dosage interval), such as from 1.5 μg/hour to 9.5 μg/hour, such asfrom 2 μg/hour to 9 μg/hour, such as from 2.5 μg/hour to 8.5 μg/hour,such as from 3 μg/hour to 8 μg/hour and including from 3.5 μg/hour to7.5 μg/hour over the course of the dosage interval.

In certain embodiments, methods include maintaining the transdermaldelivery device in contact with the subject in a manner sufficient toprovide a peak rate of dexmedetomidine delivery at specific times duringtreatment. For instance, methods may include applying a transdermaldelivery device containing a dexmedetomidine composition and maintainingthe transdermal delivery device in contact with the subject in a mannersufficient to achieve a peak rate of dexmedetomidine delivery to thesubject at about 0.5 hours or later after applying the transdermaldelivery device to the subject, such as at about 1 hour or later, suchas at about 1.5 hours or later, such as at about 2 hours or later, suchas at about 2.5 hours or later, such as at about 3 hours or later, suchas at about 3.5 hours or later and including maintaining the transdermaldelivery device in contact with the subject in a manner sufficient toachieve a peak rate of dexmedetomidine delivery to the subject at about4 hours or later after applying the transdermal delivery device to thesubject. In some instances, the method include applying a transdermaldelivery device containing a dexmedetomidine composition and maintainingthe transdermal delivery device in contact with the subject in a mannersufficient to achieve a peak rate of dexmedetomidine delivery to thesubject at from 0.5 hours to 4 hours after applying the transdermaldelivery device to the subject, such as from about 0.75 hours to 3.75hours, such as from about 1 hour to about 3.5 hours, such as from about1.25 hours to about 3.25 hours and including as from about 1.5 hours toabout 3 hours after applying the transdermal delivery device to thesubject.

In some embodiments, a peak concentration of dexmedetomidine delivery tothe subject is achieved at about 3 hours after applying the transdermaldelivery device to the subject. In other embodiments, a peakconcentration of dexmedetomidine delivery to the subject is achieved atabout 4 hours after applying the transdermal delivery device to thesubject.

The peak rate of delivery may vary depending on the physiology of thesubject and desired treatment protocol and may be 0.1 μg/cm²/hr orgreater, such as 0.2 μg/cm²/hr or greater, such as 0.3 μg/cm²/hr orgreater, such as 0.5 μg/cm²/hr, such as 0.9 μg/cm²/hr, such as 1.5μg/cm²/hr or greater, such as 2.5 μg/cm²/hr or greater, such as 1.75μg/cm²/hr or greater and including 4.5 μg/cm²/hr or greater. For peakflux of transdermal dexmedetomidine delivery, an upper limit is, in someinstances, 10 μg/cm²/hr or or less, such as 9 μg/cm²/hr or or less, suchas 8 μg/cm²/hr or or less, such as 7 μg/cm²/hr or or less, 6 μg/cm²/hror or less, such as 5 μg/cm²/hr or or less and including 2 μg/cm²/hr oror less. In certain embodiments, the peak flux of transdermaldexmedetomidine delivery ranges such as from 0.5 μg/cm²/hr to 10μg/cm²/hr, such as from 1 μg/cm²/hr to 9 μg/cm²/hr and including from 2μg/cm²/hr to 8 μg/cm²/hr.

Methods according to certain embodiments may include applying to thesubject a transdermal delivery device containing a dexmedetomidinecomposition and maintaining the transdermal dexmedetomidine compositionin contact with the subject in a manner sufficient to maintain atransdermal dexmedetomidine flux which is within 30% or more of the peaktransdermal dexmedetomidine flux after reaching the peak transdermalflux. As such, once transdermal delivery devices of interest reach peaktransdermal dexmedetomidine flux, the transdermal delivery device isconfigured to maintain a flux of dexmedetomidine to the subject that isat least 30% of peak flux during the course of any given dosageinterval, such as at least 35%, such as at least 40% and including atleast 50% of peak flux during the course of any given dosage interval.In other words, once peak flux is reached by the transdermal deliverydevice according to these particular embodiments, the transdermal fluxof dexmedetomidine to the subject does not fall below 30% or more of thepeak flux at any time during the dosage interval.

For example, the transdermal dexmedetomidine composition may bemaintained in contact with the subject in a manner sufficient tomaintain the transdermal dexmedetomidine flux which is within 80% ormore of peak transdermal dexmedetomidine flux, such as within 85% ormore, such as within 90% or more, such as within 95% and includingwithin 99% of peak transdermal dexmedetomidine flux after reaching peaktransdermal flux. In certain embodiments, the transdermaldexmedetomidine flux does not decrease at all after reaching peak fluxand maintains a rate of 100% of peak dexmedetomidine flux from themoment it reaches peak flux until the end of a given dosage interval.

In certain embodiments, methods include determining the transdermaldexmedetomidine flux. The transdermal dexmedetomidine flux may bedetermined using any convenient protocol, such for example by protocolsemploying human cadaver skin with epidermal layers (stratum corneum andepidermis) in a Franz cell having donor and receptor sides clampedtogether and receptor solution containing phosphate buffer. In someinstances, the flux of the dexmedetomidine can be determined by theequation:

J _(skin flux) =P×C   (1)

where J is the skin flux, C is the concentration gradient across theskin or mucous membrane and P is the permeability coefficient. Skin fluxis the change in cumulative amount of drug entering the body across theskin or mucous membrane with respect to time.

The amount of permeated dexmedetomidine can further be characterized byliquid chromatography. The transdermal dexmedetomidine flux may bedetermined at any time during methods of the invention. In someembodiments, the transdermal dexmedetomidine flux may be monitoredthroughout the entire time the transdermal dexmedetomidine compositionis maintained in contact with the permeation barrier (e.g., humancadaver skin), such by real-time data collection. In other instances,the transdermal dexmedetomidine flux is monitored by collecting data atregular intervals, e.g., collecting data every 0.25 hours, every 0.5hours, every 1 hour and including every 2 hours or some other interval.In yet other instances, the transdermal dexmedetomidine flux ismonitored by collecting data according to a particular time schedule.For instance, the transdermal dexmedetomidine flux may be determined 15minutes after applying the transdermal delivery device, 30 minutes afterapplying the transdermal delivery device, 1 hour after applying thetransdermal delivery device, 2 hours after applying the transdermaldelivery device and including 3 hours after applying the transdermaldelivery device.

The transdermal dexmedetomidine flux may be determined one or more timesat any given measurement period, such as 2 or more times, such as 3 ormore times, including 5 or more times at each measurement period. Anupper limit for the number of times the transdermal dexmedetomidine fluxis determined is, in some instances, 10 times or fewer, such as 7 timesor fewer, such as 5 times or fewer, such as 3 times or fewer andincluding 2 times or fewer. In certain embodiments, the number of timesthe transdermal dexmedetomidine flux is determined ranges such as from 2times to 10 times, such as from 3 times to 9 times, such as from 4 timesto 8 times and including from 5 times to 7 times.

As such, where the transdermal dexmedetomidine composition is maintainedin contact with the subject in a manner sufficient to provide atransdermal dexmedetomidine flux which is within at least 30% of peaktransdermal dexmedetomidine flux, the transdermal composition may bemaintained in contact with the subject in a manner sufficient to providea flux which is 0.15 μg/cm²/hr or greater after reaching a peaktransdermal flux of 0.5 μg/cm²/hr, such as 0.18 μg/cm²/hr or greaterafter reaching a peak transdermal flux of 0.6 μg/cm²/hr, such as 0.225μg/cm²/hr or greater after reaching a peak transdermal flux of 0.75μg/cm²/hr, such as 0.27 μg/cm²/hr or greater after reaching a peak fluxof 0.9 μg/cm²/hr, such as 0.3 μg/cm²/hr or greater after reaching a peakflux of 1.0 μg/cm²/hr, such as 1.5 μg/cm²/hr after reaching a peak fluxof 5 μg/cm²/hr or greater and including maintaining the transdermaldexmedetomidine composition in contact with the subject in a mannersufficient to provide a flux which is 3.0 μg/cm²/hr or greater afterreaching a peak flux of 10.0 μg/cm²/hr.

In certain embodiments, during treatment the transdermal composition ismaintained in contact with the subject sufficient to provide a steadystate average flux of dexmedetomidine to the subject. The term “steadystate” is used in its conventional sense to mean that the amount ofdexmedetomidine released from the transdermal composition maintains asubstantially constant average flux of dexmedetomidine. As such, thedexmedetomidine flux from transdermal delivery devices of interestincreases or decreases by 30% or less at any time while the transdermaldelivery device is maintained in contact with the subject, such as 20%or less, such as 15% or less, such as 12% or less, such as 10% or less,such as 6% or less, such as 5% or less, such as 4% or less, andincluding 1% or less at any time while the transdermal delivery deviceis maintained in contact with the subject.

In these embodiments, the transdermal delivery device is configured toprovide a constant flux, such as by introducing a concentration gradientacross the skin or mucous membrane or providing an excess indexmedetomidine dosage amount. For example, dexmedetomidine transdermalcompositions of interest may include a dexmedetomidine dosage that is 5%or greater in excess of the normal dosage amount, such as 10% orgreater, such as 15% or greater, such as 20% or greater, and including25% or greater in excess of the normal dosage amount. For amount ofexcess dexmedetomidine present in the transdermal delivery device toprovide a constant flux, an upper limit is, in some instances 50% orless in excess, such as 45% or less in excess, such as 25% or less inexcess, such as 20% or less in excess and including 10% or less inexcess of the normal dosage amount. While dexmedetomidine transdermalcompositions of interest may include an excess in order to provide aconstant flux, the excess dosage amount is not absorbed as part of thedosage interval. As such, in some embodiments where the transdermaldexmedetomidine composition is maintained in a manner sufficient toprovide a constant flux, 25% or less of the available dexmedetomidine inthe transdermal composition may not be utilized, such as 20% or less,such as 15% or less, such as 10% or less, such as 5% or less andincluding 1% or less of the available dexmedetomidine in the transdermalcomposition may not be utilized during the dosage interval.

In some embodiments, in maintaining the dexmedetomidine transdermalcomposition in contact with the subject the average cumulative amount ofpermeated dexmedetomidine increases at a substantially linear rate overthe course of the dosage interval (e.g., 7 days or longer). By“substantially linearly” is meant that the cumulative amount ofdexmedetomidine released from the transdermal composition increases at asubstantially constant rate (i.e., defined by zero-order kinetics). Assuch, the change in rate of cumulative permeated dexmedetomidineincreases or decreases by 10% or less at any given time whilemaintaining the transdermal composition in contact with the subject,such as 8% or less, such as 7% or less, such as 6% or less, such as 5%or less, such as 3% or less, such as 2.5% or less, such as 2% or less,and including 1% or less at any time while maintaining thedexmedetomidine transdermal composition in contact with the subject.

Methods for treating ADHD, anxiety and insomnia in a subject accordingto certain embodiments may also include applying a transdermal deliverydevice containing a dexmedetomidine composition and maintaining thetransdermal dexmedetomidine composition in contact with the subject in amanner sufficient to deliver an amount of dexmedetomidine to a subjectwhich provides a mean plasma concentration which ranges from 0.01 ng/mLto 0.4 ng/mL over the course of a dosage interval, such as from 0.05ng/mL to 0.35 ng/mL, such as from 0.15 ng/mL to 0.4 ng/mL, such as from0.2 ng/mL to 0.35 ng/mL and including from 0.25 ng/mL to 0.3 ng/mL overthe course of the dosage interval. For example, the transdermal deliverydevice may be maintained in contact with the subject in a mannersufficient to provide a mean plasma concentration which ranges from 0.16ng/mL to 0.36 ng/mL over the course of a dosage interval (e.g., an 8hour or longer dosage interval).

In certain embodiments, methods include maintaining the transdermaldelivery device in contact with the subject in a manner sufficient toprovide a desired plasma concentration of dexmedetomidine at specifictimes during treatment. For instance, methods may include applying tothe subject a transdermal delivery device containing a dexmedetomidinecomposition and maintaining the transdermal delivery device in contactwith a subject in a manner sufficient to achieve a peak plasmaconcentration of dexmedetomidine in the subject at about 2 hours orlater after applying the transdermal delivery device to the subject,such as at about 2.5 hours or later, such as at about 3 hours or later,such as at about 3.5 hours or later, such as at about 4 hours or later,such as at about 4.5 hours or later and including maintaining thetransdermal delivery device in contact with a subject in a mannersufficient to achieve a peak plasma concentration of dexmedetomidine inthe subject at about 5 hours or later after applying the transdermaldelivery device to the subject. In some embodiments, a peak plasmaconcentration of dexmedetomidine in the subject is achieved at about 3hours or later after applying the transdermal delivery device to thesubject. In other embodiments, a peak plasma concentration ofdexmedetomidine in the subject is achieved at about 5 hours or laterafter applying the transdermal delivery device to the subject.

In certain embodiments, methods may also include determining the plasmaconcentration of dexmedetomidine during treatment. The plasmaconcentration may be determined using any convenient protocol, such forexample by liquid chromatography-mass spectrometry (LCMS). The plasmaconcentration of the dexmedetomidine may be determined at any timedesired. In some embodiments, the plasma concentration ofdexmedetomidine may be monitored throughout the entire time thetransdermal delivery device is maintained in contact with the subject,such by real-time data collection. In other instances, the plasmaconcentration of dexmedetomidine is monitored while maintaining thetransdermal delivery device in contact with the subject by collectingdata at regular intervals, e.g., collecting data every 0.25 hours, every0.5 hours, every 1 hour including every 2 hours, or some other interval.In yet other instances, the plasma concentration of dexmedetomidine ismonitored while maintaining the transdermal delivery device in contactwith the subject by collecting data according to a particular timeschedule after applying the transdermal delivery device to the subject.For instance, the plasma concentration of dexmedetomidine may bedetermined 15 minutes after applying the transdermal delivery device tothe subject, 30 minutes after applying the transdermal delivery deviceto the subject, 1 hour after applying the transdermal delivery device tothe subject, 2 hours after applying the transdermal delivery device tothe subject and including 3 hours after applying the transdermaldelivery device to the subject.

In certain embodiments, the plasma concentration of dexmedetomidine isdetermined before the transdermal delivery device is applied to asubject, such as for example, to determine the basal plasmaconcentration of the dexmedetomidine. For example, the plasmaconcentration may be determined 5 minutes before applying thetransdermal delivery device, such as 10 minutes before, such as 30minutes before, such as 60 minutes before and including 120 minutesbefore applying the transdermal delivery device. As described above,methods may include multiple dosage intervals where applying andmaintaining the transdermal delivery device in contact with the subjectmay be repeated. In these embodiments, the plasma concentration may bedetermined after a first transdermal delivery device is removed andbefore a second transdermal delivery device is applied.

The blood plasma concentration of the dexmedetomidine may be determinedone or more times at any given measurement period, such as 2 or moretimes, such as 3 or more times, including 5 or more times at eachmeasurement period. An upper limit for the number of times the bloodplasma concentration of dexmedetomidine is determined at any givenmeasurement period is, in some instances, 10 times or fewer, such as 7times or fewer, such as 5 times or fewer, such as 3 times or fewer andincluding 2 times or fewer. In certain embodiments, the number of timesthe blood plasma concentration of dexmedetomidine is determined at anygiven measurement period ranges such as from 2 times to 10 times, suchas from 3 times to 9 times, such as from 4 times to 8 times andincluding from 5 times to 7 times.

As described above, aspects of the invention include treating ADHD,anxiety or insomnia in a subject by applying a transdermal deliverydevice containing a dexmedetomidine composition and maintaining thetransdermal dexmedetomidine composition in contact with the subject. Insome embodiments, methods for treating ADHD, anxiety or insomnia in asubject may include maintaining the transdermal composition in contactwith the subject in a manner sufficient to deliver a predeterminedamount of dexmedetomidine to the subject. Where protocols includedelivering a predetermined amount of dexmedetomidine to the subject, theamount of dexmedetomidine in the compositions of interest may range from0.001 mg to 10 mg, such as 0.005 to 9.5 mg, such as 0.01 mg to 8.5 mg,such as 0.05 to 8 mg, such as 0.1 mg to 7.5 mg, such as 0.5 mg to 7 mgand including from 1 mg to 5 mg.

In certain embodiments, the predetermined amount of dexmedetomidinedelivered to the subject may be a percentage of the total amount ofdexmedetomidine present in the compositions. For instance, thepredetermined amount of dexmedetomidine delivered to the subject may be5% or greater of the total amount of dexmedetomidine present in thecomposition, such as 10% or greater, such as 25% or greater, such as 40%or greater, such as 45% or greater and including 50% or greater of thetotal amount of dexmedetomidine present in the composition. Forutilization percentage, an upper limit over the course of a dosageinterval is, in some instances, 90% or less, such as 75% or less, suchas 50% or less and including 25% or less over the course of a dosageinterval.

For example, where the transdermal dexmedetomidine composition contains10 mg of dexmedetomidine, methods may include maintaining thetransdermal delivery device in contact with the subject in a mannersufficient to deliver 0.5 mg or more of dexmedetomidine in thetransdermal composition over the course of the dosage interval, such as1.0 mg or more, such as 2.5 mg or more, such as 4.5 mg or more, such as5.5 mg or more and including maintaining the transdermal delivery devicein contact with the subject in a manner sufficient to deliver 5 mg ormore of dexmedetomidine in the transdermal composition.

In certain embodiments, the predetermined amount of dexmedetomidinedelivered to the subject may be a percentage of the total amount ofdexmedetomidine present in the dexmedetomidine transdermal compositions.For instance, the predetermined amount of dexmedetomidine delivered tothe subject may be 1% or greater of the total amount of dexmedetomidinepresent in the dexmedetomidine transdermal composition, such as 2% orgreater, such as 5% or greater, such as 10% or greater, such as 25% orgreater and including 50% or greater of the total amount ofdexmedetomidine present in the dexmedetomidine transdermal composition.In other words, methods may include maintaining the dexmedetomidinetransdermal composition in contact with the subject in a mannersufficient to deliver 5% or greater of the dexmedetomidine in thedexmedetomidine transdermal composition to the subject over the courseof a single dosage interval. In these embodiments, the utilizationpercentage of dexmedetomidine is 5% or greater during the time thetransdermal delivery device is maintained in contact with the subject.As such, 95% or less of the original amount of dexmedetomidine remainsin the dexmedetomidine transdermal composition after a dosage interval.As described in greater detail below, the subject transdermal deliverydevices are capable of high utilization percentage. In other words, thesubject transdermal delivery devices are capable of deliveringdexmedetomidine to the subject leaving little residual dexmedetomidinein the transdermal delivery device after a given dosage interval. Theutilization percentage may be 5% or greater over the course of a dosageinterval, such as 10% or greater, such as 25% or greater, such as 40% orgreater, such as 45% or greater and including 50% or greater of thedexmedetomidine over the course of a dosage interval. For utilizationpercentage, an upper limit over the course of a dosage interval is, insome instances, 90% or less, such as 50% or less, such as 25% or lessand including 5% or less over the course of a dosage interval.

For instance, where the subject dexmedetomidine transdermal compositioncontains 1 mg of dexmedetomidine, methods may include maintaining thetransdermal delivery device in contact with the subject in a mannersufficient to deliver 0.05 mg or more of dexmedetomidine in thedexmedetomidine transdermal composition over the course of the dosageinterval (e.g., 7 days or longer), such as 0.1 mg or more, such as 0.25mg or more, such as 0.4 mg or more, such as 0.45 mg or more andincluding maintaining the transdermal delivery device in contact withthe subject in a manner sufficient to deliver 0.5 mg or more ofdexmedetomidine in the dexmedetomidine composition. As such, 0.95 mg orless of dexmedetomidine remains in the dexmedetomidine transdermalcomposition after 7 days or longer, such as 0.9 mg or less, such as 0.75mg or less, such as 0.6 mg or less and including 0.5 mg or less ofdexmedetomidine remains in the dexmedetomidine transdermal compositionafter the dosage interval.

As described in greater detail below, in certain embodiments transdermaldelivery devices include a single layer matrix dexmedetomidinecomposition which is configured to deliver an amount of dexmedetomidinesufficient to treat ADHD, anxiety or insomnia in a subject. As such,methods according to certain instance include applying a transdermaldelivery device having a single layer matrix dexmedetomidine compositionand maintaining the single layer dexmedetomidine composition in contactwith the subject over a period of time sufficient to deliver an amountof dexmedetomidine sufficient to treat ADHD, anxiety and insomnia in thesubject.

In certain embodiments, each of the subject methods described in greaterdetail below may further include the step of removing the transdermaldelivery device from contact with the subject at the conclusion of adosage interval. For example, the transdermal delivery device may beremoved from contact with the subject after maintaining the transdermaldelivery device in contact with the subject for 0.5 hours or more, suchas 1 hour or more, such as 2 hours or more, such as 4 hours or more,such as 8 hours or more, such as 12 hours or more and including 24 hoursor more. An upper limit for the amount of time the transdermal deliverydevice is maintained in contact with a subject before removal is, insome instances, 24 hours or shorter, such as 20 hours or shorter, suchas 16 hours or shorter, such as 12 hours or shorter, such as 8 hours orshorter, such as 4 hours or shorter, such as 3 hours or shorter, such as2 hours or shorter and including 1 hour or shorter.

By “removing” the transdermal delivery device from contact with thesubject is meant that no amount of dexmedetomidine from the transdermalcomposition remains in contact with the subject, including any residualamount of dexmedetomidine left behind on the surface of the skin ormucous membrane when the transdermal delivery device was applied. Inother words, when the transdermal delivery device is removed all tracesof dexmedetomidine are no longer on the surface of the skin or mucousmembrane at the application site, resulting in zero transdermal flux ofdexmedetomidine into the subject.

As described above, a dosage interval is a single administration ofapplying and maintaining the transdermal delivery device in contact withthe subject which begins with applying the transdermal dexmedetomidinecomposition to the skin or mucous membrane of the subject and ends withthe removal of the transdermal delivery device from contact with thesubject. In certain embodiments, protocols for may include multipledosage intervals. By “multiple dosage intervals” is meant more than onetransdermal delivery device is applied and maintained in contact withthe subject in a sequential manner. As such, a transdermal deliverydevice is removed from contact with the subject and a new transdermaldelivery device is reapplied to the subject. In practicing methods ofthe invention, treatment regimens may include two or more dosageintervals, such as three or more dosage intervals, such as four or moredosage intervals, such as five or more dosage intervals, including tenor more dosage intervals.

The location on the subject for reapplying subsequent transdermaldelivery devices in multiple dosage treatment regimens may be the sameor different from the location on the subject where the previoustransdermal delivery device was removed. For example, if a firsttransdermal delivery device is applied and maintained on the leg of thesubject, one or more subsequent transdermal delivery devices may bereapplied to the same position on the leg of the subject. On the otherhand, if a first transdermal delivery device was applied and maintainedon the leg of the subject, one or more subsequent transdermal deliverydevice may be reapplied to a different position, such as the abdomen orback of the subject. Subsequent dosages applied in multiple dosageinterval regimens may have the same or different formulation ofdexmedetomidine. In certain instances, a subsequent dosage interval in atreatment regimen may contain a higher or lower concentration ofdexmedetomidine than the previous dosage interval. For example, theconcentration of dexmedetomidine may be increased in subsequent dosageintervals by 10% or greater, such as 20% or greater, such as 50% orgreater, such as 75% or greater, such as 90% or greater and including100% or greater. An upper limit for the increase in concentration ofdexmedetomidine in subsequent dosage intervals is, in some instances,10-fold or less, such as 5-fold or less, such as 2-fold or less, such as1-fold or less, such as 0.5-fold or less and including 0.25-fold orless.

On the other hand, the concentration of dexmedetomidine may be decreasedin subsequent dosage intervals, such as by 10% or greater, such as 20%or greater, such as 50% or greater, such as 75% or greater, such as 90%or greater and including 100% or greater. An upper limit for thedecrease in concentration of dexmedetomidine in subsequent dosageintervals is, in some instances, 10-fold or less, such as 5-fold orless, such as 2-fold or less, such as 1-fold or less, such as 0.5-foldor less and including 0.25-fold or less.

In other instances, a subsequent dosage interval may contain a differentformulation of dexmedetomidine than the previous dosage interval, suchas a different pressure sensitive adhesive or the presence or absence ofa permeation enhancer, as described in greater detail below.

In certain embodiments, compositions of the invention can beadministered prior to, concurrent with, or subsequent to othertherapeutic agents for treating the same or an unrelated condition. Ifprovided at the same time as another therapeutic agent, the subjectdexmedetomidine compositions may be administered in the same or in adifferent composition. Thus, dexmedetomidine compositions of interestand other therapeutic agents can be administered to the subject by wayof concurrent therapy. By “concurrent therapy” is intendedadministration to a subject such that the therapeutic effect of thecombination of the substances is caused in the subject undergoingtherapy. For example, concurrent therapy may be achieved byadministering dexmedetomidine compositions of the invention with apharmaceutical composition having at least one other agent, such as ananalgesic (such as an opioid), anesthetic, antihypertensive,chemotherapeutic, among other types of therapeutics, which incombination make up a therapeutically effective dose, according to aparticular dosing regimen. Administration of the separate pharmaceuticalcompositions can be performed simultaneously or at different times(i.e., sequentially, in either order, on the same day, or on differentdays), so long as the therapeutic effect of the combination of thesesubstances is caused in the subject undergoing therapy.

Where dexmedetomidine is administered concurrently with a secondtherapeutic agent to treat the same condition, the weight ratio ofdexmedetomidine to second therapeutic agent may range from 1:2 and1:2.5; 1:2.5 and 1:3; 1:3 and 1:3.5 1:3.5 and 1:4; 1:4 and 1:4.5; 1:4.5and 1:5; 1:5 and 1:10; and 1:10 and 1:25 or a range thereof. Forexample, the weight ratio of dexmedetomidine to second therapeutic agentmay range between 1:1 and 1:5; 1:5 and 1:10; 1:10 and 1:15; or 1:15 and1:25. Alternatively, the weight ratio of the second therapeutic agent todexmedetomidine ranges between 2:1 and 2.5:1; 2.5:1 and 3:1; 3:1 and3.5:1; 3.5:1 and 4:1; 4:1 and 4.5:1; 4.5:1 and 5:1; 5:1 and 10:1; and10:1 and 25:1 or a range thereof. For example, the ratio of the secondtherapeutic agent dexmedetomidine may range between 1:1 and 5:1; 5:1 and10:1; 10:1 and 15:1; or 15:1 and 25:1.

Dexmedetomidine Transdermal Delivery Devices Containing aDexmedetomidine Composition for Treating a Subject for ADHD, Anxiety orInsomnia

Aspects of the invention also include dexmedetomidine transdermaldelivery devices for delivering an amount of dexmedetomidine to asubject suitable for practicing the subject methods. Transdermaldelivery devices of interest include a composition havingdexmedetomidine and a pressure sensitive adhesive. Dexmedetomidine isthe S-enantiomer of medetomidine described by the formula:

Dexmedetomidine according to embodiments of the invention may be in theform of a free base, salt, solvate, hydrate or complex. For example,dexmedetomidine may be in the form of a pharmaceutically acceptable saltincluding, but not limited to, a mesylate, maleate, fumarate, tartrate,hydrochloride, hydrobromide, esylate, p-toluenesulfonate, benzoate,acetate, phosphate and sulfate salt. Dexmedetomidine according to someembodiments may be a free base. In other instances, dexmedetomidine mayform a complex.

Depending on the site of application and the physiology of the subject(e.g., body mass), the amount of dexmedetomidine in compositions ofinterest may vary, in some instances, the amount of dexmedetomidineranges from 0.001 mg to 50 mg, such as 0.005 mg to 40 mg, such as 0.01to 30 mg, such as 0.05 to 20 mg, and including 0.1mg to 10 mg. In someembodiments, the amount of dexmedetomidine in the transdermalcomposition ranges from 0.1% to 20% w/w, such as 0.5% to 18% w/w, suchas 1% to 15%, such as 2% to 12.5% w/w and including 3% to 10% w/w. Inother embodiments, the amount of dexmedetomidine in the subjecttransdermal compositions is 10% by weight or less of the total weight ofthe transdermal composition, such as 9% by weight or less, such as 8% byweight or less, such as 7% by weight or less, such as 6% by weight orless, such as 5% by weight or less and including 3% by weight or less ofthe total weight of the transdermal composition. In certain embodiments,dexmedetomidine compositions include an amount which is below thesaturation point of dexmedetomidine. In other embodiments,dexmedetomidine compositions include a saturated amount ofdexmedetomidine. In yet other embodiments, dexmedetomidine compositionsinclude a supersaturated amount of dexmedetomidine.

In certain embodiments, dexmedetomidine compositions described hereinare formulated to deliver a sedative amount of dexmedetomidine. Asdescribed above, by sedative is meant that the dexmedetomidinecomposition is formulated to deliver an amount of dexmedetomidine to thesubject which causes at least partial sedation. In certain embodiments,transdermal delivery devices include dexmedetomine compositionsformulated to deliver an amount of dexmedetomidine to the subject suchthat the subject is characterized as being in a state where the subjectcan exhibit brisk response to light glabellar tap or loud auditorystimulus. In other instances, transdermal delivery devices includedexmedetomine compositions formulated to deliver an amount ofdexmedetomidine to the subject such that the subject exhibits a sluggishresponse to light glabellar tap or loud auditory stimulus. In certaininstances, transdermal delivery devices include a dexmedetomidinecomposition formulated to deliver an amount of dexmedetomidine which isfully sedative and the subject is characterized as being in a statewhere the subject exhibits no response to touch or auditory stimulus.

As described in greater detail below, in some embodimentsdexmedetomidine transdermal compositions of interest are formulated suchthat throughout transdermal administration the subject may be evaluatedaccording to the Ramsey Sedation Scale and assigned a Ramsey score of 2or higher, such as 3 or higher, such as 4 or higher and including aRamsey score of 5. For example, methods may include delivering an amountof dexmedetomidine to the subject in manner sufficient to maintain aRamsay score of between 2 and 5 in the subject, such as between 3 and 5and including a Ramsay score of between 4 and 5.

In embodiments of the present invention, transdermal dexmedetomidinecompositions also include a pressure sensitive adhesive. Pressuresensitive adhesives may include, but are not limited to, poly-isobuteneadhesives, poly-isobutylene adhesives, poly-isobutene/polyisobutyleneadhesive mixtures, carboxylated polymers, acrylic or acrylatecopolymers, such as carboxylated acrylate copolymers.

Where the pressure sensitive adhesive includes polybutene, thepolybutene may be saturated polybutene. Alternatively, the polybutenemay be unsaturated polybutene. Still further, the polybutene may be amixture or combination of saturated polybutene and unsaturatedpolybutene. In some embodiments, the pressure sensitive adhesive mayinclude a composition that is, or is substantially the same as, thecomposition of Indopol® L-2, Indopol® L-3, Indopol® L-6, Indopol® L-8,Indopol® L-14, Indopol® H-7, Indopol® H-8, Indopol® H-15, Indopol® H-25,Indopol® H-35, Indopol® H-50, Indopol® H-100, Indopol® H-300, Indopol®H-1200, Indopol® H-1500, Indopol® H-1900, Indopol® H-2100, Indopol®H-6000, Indopol® H-18000, Panalane® L-14E, Panalane® H-300E andcombinations thereof. In certain embodiments, the polybutenepressure-sensitive adhesive is Indopol® H-1900. In other embodiments,the polybutene pressure-sensitive adhesive is Panalane® H-300E.

Acrylate copolymers of interest include copolymers of various monomers,such as “soft” monomers, “hard” monomers or “functional” monomers. Theacrylate copolymers can be composed of a copolymer including bipolymer(i.e., made with two monomers), a terpolymer (i.e., made with threemonomers), or a tetrapolymer (i.e., made with four monomers), orcopolymers having greater numbers of monomers. The acrylate copolymersmay be crosslinked or non-crosslinked. The polymers can be cross-linkedby known methods to provide the desired polymers. The monomers from ofthe acrylate copolymers may include at least two or more exemplarycomponents selected from the group including acrylic acids, alkylacrylates, methacrylates, copolymerizable secondary monomers or monomerswith functional groups. Monomers (“soft” and “hard” monomers) may bemethoxyethyl acrylate, ethyl acrylate, butyl acrylate, butylmethacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate,2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate,2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decylmethacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate,tridecyl methacrylate, acrylonitrile, methoxyethyl acrylate,methoxyethyl methacrylate, and the like. Additional examples of acrylicadhesive monomers are described in Satas, “Acrylic Adhesives,” Handbookof Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 396-456 (D.Satas, ed.), Van Nostrand Reinhold, New York (1989), the disclosure ofwhich is herein incorporated by reference. In some embodiments, thepressure sensitive adhesive is an acrylate-vinyl acetate copolymer. Insome embodiments, the pressure sensitive adhesive may include acomposition that is, or is substantially the same as, the composition ofDuro-Tak® 87-9301, Duro-Tak® 87-200A, Duro-Tak®87-2353,Duro-Tak®87-2100, Duro-Tak®87-2051, Duro-Tak®87-2052, Duro-Tak®87-2194,Duro-Tak®87-2677, Duro-Tak®87-201A, Duro-Tak®87-2979, Duro-Tak®87-2510,Duro-Tak®87-2516, Duro-Tak®87-387, Duro-Tak®87-4287,Duro-Tak®87-2287,and Duro-Tak®87-2074 and combinations thereof. The term“substantially the same” as used herein refers to a composition that isan acrylate-vinyl acetate copolymer in an organic solvent solution. Incertain embodiments, the acrylic pressure-sensitive adhesive isDuro-Tak® 87-2054.

In certain embodiments, the pressure sensitive adhesive is an acrylateadhesive that is a non-functionalized acrylate, hydroxyl-functionalizedacrylate or an acid functionalized acrylate. For example, the acrylateadhesive may be an acrylic adhesive having one or more —OH functionalgroups. Where the acrylic adhesive has one or more —OH functionalgroups, in some instances, the pressure sensitive adhesive may be acomposition that is, or is substantially the same as, the composition ofDuro-Tak® 87-4287, Duro-Tak® 87-2287, Duro-Tak® 87-2510 and Duro-Tak®87-2516 and combinations thereof. The acrylate adhesive mayalternatively be an acrylic adhesive having one or more —COOH functionalgroups. Where the acrylic adhesive has one or more —COOH functionalgroups, in some instances, the pressure sensitive adhesive may be acomposition that is or is substantially the same as, the composition ofDuro-Tak® 87-387, Duro-Tak® 87-2979 and Duro-Tak® 87-2353 andcombinations thereof. Still further, the acrylate adhesive may be anon-functionalized acrylic adhesive. Where the acrylic adhesive isnon-functionalized, in some instances the pressure sensitive adhesivemay be a composition that is or is substantially the same as, thecomposition of Duro-Tak® 87-9301.

The amount of pressure sensitive adhesive in transdermal dexmedetomidinecompositions of interest may vary, the amount of pressure sensitiveadhesive ranging from 0.1 mg to 2000 mg, such as 0.5 mg to 1500 mg, suchas 1 to 1000 mg, such as 10 to 750 mg, and including 10 mg to 500 mg. Assuch, the amount of pressure sensitive adhesive in the transdermalcomposition ranges from 1% to 99% w/w, such as 5% to 95% w/w, such as10% to 95%, such as 15% to 90% w/w and including 20% to 85% w/w. Inother embodiments, the amount of pressure sensitive adhesive in thesubject transdermal compositions is 70% by weight or greater of thetotal weight of the transdermal composition, such as 75% by weight orgreater, such as 80% by weight or greater, such as 85% by weight orgreater, such as 90% by weight or greater, such as 95% by weight orgreater and including 97% by weight or greater of the total weight ofthe transdermal composition.

The weight ratio of pressure sensitive adhesive to dexmedetomidine inthe subject compositions may range from 1:2 and 1:2.5; 1:2.5 and 1:3;1:3 and 1:3.5 1:3.5 and 1:4; 1:4 and 1:4.5; 1:4.5 and 1:5; 1:5 and 1:10;1:10 and 1:25; 1:25 and 1:50; 1:50 and 1:75; and 1:75 and 1:99 or arange thereof. For example, the weight ratio of pressure sensitiveadhesive to dexmedetomidine in compositions of interest may rangebetween 1:1 and 1:5; 1:5 and 1:10; 1:10 and 1:15; 1:15 and 1:25; 1:25and 1:50; 1:50 and 1:75 or 1:75 and 1:99. Alternatively, the weightratio of dexmedetomidine to pressure sensitive adhesive in the subjectcompositions ranges between 2:1 and 2.5:1; 2.5:1 and 3:1; 3:1 and 3.5:1;3.5:1 and 4:1; 4:1 and 4.5:1; 4.5:1 and 5:1; 5:1 and 10:1; 10:1 and25:1; 25:1 and 50:1; 50:1 and 75:1; and 75:1 and 99:1 or a rangethereof. For example, the ratio of dexmedetomidine to pressure sensitiveadhesive in compositions of interest may range between 1:1 and 5:1; 5:1and 10:1; 10:1 and 15:1; 15:1 and 25:1; 25:1 and 50:1; 50:1 and 75:1; or75:1 and 99:1.

In some embodiments, transdermal dexmedetomidine compositions mayfurther include one or more crosslinked hydrophilic polymers. Forexample, the crosslinked polymer may be an amine-containing hydrophilicpolymer. Amine-containing polymers may include, but are not limited to,polyethyleneimine, amine-terminated polyethylene oxide, amine-terminatedpolyethylene/polypropylene oxide, polymers of dimethyl amino ethylmethacrylate, and copolymers of dimethyl amino ethyl methacrylate andvinyl pyrrolidone. In certain embodiments, the crosslinked polymer iscrosslinked polyvinylpyrrolidone, such as for example PVP-CLM.

The matrix may contain other additives depending on the adhesive used.For example, materials, such as PVP-CLM, PVP K17, PVP K30, PVP K90, thatinhibit drug crystallization, have hygroscopic properties that improvethe duration of wear, and improve the physical properties, e.g., coldflow, tack, cohesive strength, of the adhesive.

The amount of crosslinked polymer in dexmedetomidine compositions ofinterest may vary, the amount of crosslinked polymer ranging from 0.1 mgto 500 mg, such as 0.5 mg to 400 mg, such as 1 to 300 mg, such as 10 to200 mg, and including 10 mg to 100 mg. As such, the amount ofcrosslinked polymer in the transdermal composition ranges from 2% to 30%w/w, such as 4% to 30% w/w, such as 5% to 25%, such as 6% to 22.5% w/wand including 10% to 20% w/w. In other embodiments, the amount ofcrosslinked polymer in the subject transdermal compositions is 8% byweight or greater of the total weight of the transdermal composition,such as 10% by weight or greater, such as 12% by weight or greater, suchas 15% by weight or greater, such as 20% by weight or greater, such as25% by weight or greater and including 30% by weight crosslinked polymeror greater of the total weight of the transdermal composition.

In certain embodiments, the subject transdermal dexmedetomidinecompositions further include a dexmedetomidine solubility enhancer. By“solubility enhancer” is meant a compound or composition which increasesthe dexmedetomidine solubility in the subject compositions, such as, forexample, to prevent any unwanted crystallization of dexmedetomidine inthe composition. The dexmedetomidine solubilization enhancer isincorporated into the dexmedetomidine composition in an amount rangingfrom 0.01% to 20% (w/w), such as from 0.05% to 15% (w/w), such as from0.1% to 10% (w/w), such as from 0.5% to 8% (w/w) and including from 1%to 5% (w/w).

Example solubility enhancers include, but are not limited to acidsincluding linolic acid, oleic acid, linolenic acid, stearic acid,isostearic acid, levulinic acid, palmitic acid, octanoic acid, decanoicacid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid,octadecanoic acid (i.e., stearic acid), N-lauroyl sarcosine,L-pyroglutamic acid, lauric acid, succinic acid, pyruvic acid, glutaricacid, sebacic acid, cyclopentane carboxylic acid; acylated amino acids.Other solubility enhancers of interest may include, but is not limitedto aliphatic alcohols, such as saturated or unsaturated higher alcoholshaving 12 to 22 carbon atoms (e.g., oleyl alcohol or lauryl alcohol);fatty acid esters, such as isopropyl myristate, diisopropyl adipate,lauryl lactate,propyl laurate, ethyl oleate and isopropyl palmitate;alcohol amines, such as triethanolamine, triethanolamine hydrochloride,and diisopropanolamine; polyhydric alcohol alkyl ethers, such as alkylethers of polyhydric alcohols such as glycerol, ethylene glycol,propylene glycol, 1,3-butylene glycol, diglycerol, polyglycerol,diethylene glycol, polyethylene glycol, dipropylene glycol,polypropylene glycol, polypropylene glycolmonolaurate, sorbitan,sorbitol, isosorbide, methyl glucoside, oligosaccharides, and reducingoligosaccharides, where the number of carbon atoms of the alkyl groupmoiety in the polyhydric alcohol alkyl ethers is preferably 6 to 20;polyoxyethylene alkyl ethers, such as polyoxyethylene alkyl ethers inwhich the number of carbon atoms of the alkyl group moiety is 6 to 20,and the number of repeating units (e.g. —O—CH₂CH₂—) of thepolyoxyethylene chain is 1 to 9, such as but not limited topolyoxyethylene lauryl ether, polyoxyethylene cetyl ether,polyoxyethylene stearyl ether, and polyoxyethylene oleyl ether;glycerides (i.e., fatty acid esters of glycerol), such as glycerolesters of fatty acids having 6 to 18 carbon atoms, where the glyceridesmay be monoglycerides (i.e., a glycerol molecule covalently bonded toone fatty acid chain through an ester linkage), diglycerides (i.e., aglycerol molecule covalently bonded to two fatty acid chains throughester linkages), triglycerides (i.e., a glycerol molecule covalentlybonded to three fatty acid chains through ester linkages), orcombinations thereof, where the fatty acid components forming theglycerides include octanoic acid, decanoic acid, dodecanoic acid,tetradecanoic acid, hexadecanoic acid, octadecanoic acid (i.e., stearicacid) and oleic acid; middle-chain fatty acid esters of polyhydricalcohols; lactic acid alkyl esters; dibasic acid alkyl esters; acylatedamino acids; pyrrolidone; pyrrolidone derivatives and combinationsthereof. Additional types of solubility enhancers may include lacticacid, tartaric acid, 1,2,6-hexanetriol, benzyl alcohol, lanoline,potassium hydroxide (KOH), tris(hydroxymethyl)aminomethane, glycerolmonooleate (GMO), sorbitan monolaurate (SML), sorbitan monooleate (SMO),laureth-4 (LTH), and combinations thereof. In certain embodiments, thesolubility absorption enhancer is levulinic acid, lauryl lactate orpropylene glycolmonolaurate.

The formulation of the subject transdermal dexmedetomidine compositionmay vary. For example, compositions of the invention may be in the formof a liquid solution or suspension, syrup, gel, foam or any combinationthereof for application by the transdermal delivery device.

In some embodiments, the transdermal delivery device is configured toinclude a single layer matrix dexmedetomidine composition. By “singlelayer” is meant that the transdermal delivery device includes only asingle layer of dexmedetomidine composition disposed on the surface of asubstrate of the transdermal delivery device and does not includeseparate distinct layers for the pressure sensitive adhesive,transdermal dexmedetomidine composition, or if present any solubilityenhancers. Likewise, single layer transdermal delivery devices of thepresent invention do not further include a separate dexmedetomidinereservoir (i.e., active agent reservoir) separate from the pressuresensitive adhesive. As such, single layer transdermal delivery devicesof the present invention may include in a single matrix an amount ofeach of the components of the transdermal dexmedetomidine compositionsnecessary for practicing the subject methods, as described in greaterdetail below. For example, in some embodiments, single layer transdermaldelivery devices of interest include a single layer matrix ofdexmedetomidine and a pressure sensitive adhesive which is configured todeliver a an amount of dexmedetomidine sufficient to treat ADHD, anxietyor insomnia in a subject. In another embodiment, single layertransdermal delivery devices of interest include a single layer matrixof dexmedetomidine, a pressure sensitive adhesive and a solubilityenhancer which is configured to deliver an amount of dexmedetomidinesufficient to treat ADHD, anxiety or insomnia in a subject. In anotherembodiment, single layer transdermal delivery devices of interestinclude a single layer matrix of dexmedetomidine, a pressure sensitiveadhesive and a fatty acid ester which is configured to deliver an amountof dexmedetomidine sufficient to treat ADHD, anxiety or insomnia in asubject. In certain embodiments, single layer transdermal deliverydevices of interest include a single layer matrix having onlydexmedetomidine and a pressure sensitive adhesive. Depending on thelength of the dosage interval and the desired target dosage, thethickness of single layer matrices of interest may vary, in someinstances ranging in thickness from 10 to 260 microns, such as 15 to 250microns, such as 25 to 225 microns, such as 50 to 200 microns, such as75 to 175 microns and including 20 to 130 microns such as 35 to 110microns.

The size of subject transdermal delivery devices may vary, in someinstances sized to cover the entire application site on the subject. Assuch, the transdermal delivery device may have a length ranging from 1to 100 cm, such as from 1 to 60 cm and a width ranging from 1 to 100 cm,such as from 1 to 60 cm. As such, the area of the transdermal deliverydevice may range from 4 cm² to 10,000 cm², such as from 5 cm² to 1000cm², such as from 10 cm² to 100 cm², such as from 15 cm² to 50 cm² andincluding from 20 cm² to 40 cm². In certain embodiments, the transdermaldelivery device is sized to have an area of 30 cm². In certaininstances, the transdermal delivery device is insoluble in water. Byinsoluble in water is meant that that the transdermal delivery devicemay be immersed in water for a period of 1 day or longer, such as 1 weekor longer, including 1 month or longer, and exhibit little if anydissolution, e.g., no observable dissolution.

In certain embodiments, the transdermal delivery device as describedabove furthers includes an overlay backing layer. The overlay backingmay be flexible, such as so that it can be brought into close contactwith the desired application site on the subject. The overlay backingmay be fabricated from a material that does not absorb thedexmedetomidine, and does not allow the dexmedetomidine to be leachedfrom the matrix. Overlay backing layers of interest may include, but arenot limited to, non-woven fabrics, woven fabrics, films (includingsheets), porous bodies, foamed bodies, paper, composite materialsobtained by laminating a film on a non-woven fabric or fabric, andcombinations thereof.

Non-woven fabric may include polyolefin resins such as polyethylene andpolypropylene; polyester resins such as polyethylene terephthalate,polybutylene terephthalate and polyethylene naphthalate; rayon,polyamide, poly(ester ether), polyurethane, polyacrylic resins,polyvinyl alcohol, styrene-isoprene-styrene copolymers, andstyrene-ethylene-propylene-styrene copolymers; and combinations thereof.Fabrics may include cotton, rayon, polyacrylic resins, polyester resins,polyvinyl alcohol, and combinations thereof. Films may includepolyolefin resins such as polyethylene and polypropylene; polyacrylicresins such as polymethyl methacrylate and polyethyl methacrylate;polyester resins such as polyethylene terephthalate, polybutyleneterephthalate and polyethylene naphthalate; and besides cellophane,polyvinyl alcohol, ethylene-vinyl alcohol copolymers, polyvinylchloride, polystyrene, polyurethane, polyacrylonitrile, fluororesins,styrene-isoprene-styrene copolymers, styrene-butadiene rubber,polybutadiene, ethylene-vinyl acetate copolymers, polyamide, andpolysulfone; and combinations thereof. Papers may include impregnatedpaper, coated paper, wood free paper, Kraft paper, Japanese paper,glassine paper, synthetic paper, and combinations thereof.

Depending on the dosage interval and the desired target dosage, the sizeof the overlay backing may vary, and in some instances sized to coverthe entire application site on the subject. As such, the backing layermay have a length ranging from 2 to 100 cm, such as 4 to 60 cm and awidth ranging from 2 to 100 cm, such as 4 to 60 cm. In certaininstances, the overlay backing layer may insoluble in water. Byinsoluble in water is meant that that the backing layer may be immersedin water for a period of 1 day or longer, such as 1 week or longer,including 1 month or longer, and exhibit little if any dissolution,e.g., no observable dissolution.

Transdermal delivery devices having a dexmedetomidine compositionaccording to embodiments of the invention are non-irritable to the skinof the subject at the site of application. Irritation of the skin isreferred to herein in its general sense to refer to adverse effects,discoloration or damage to the skin, such as for example, redness, pain,swelling or dryness. As such, in practicing methods with the subjecttransdermal delivery devices the quality of the skin remains normal andtransdermal delivery is consistent throughout the entire dosageinterval.

In some embodiments, skin irritation is evaluated to determine thequality and color of the skin at the application site and to determinewhether any damage, pain, swelling or dryness has resulted frommaintaining the transdermal composition in contact with the subject. Theskin may be evaluated for irritation by any convenient protocol, such asfor example using the Draize scale, as disclosed in Draize, J. H.,Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics, pp.46-49, The Association of Food and Drug Officials of the United States:Austin, Tex., the disclosure of which is herein incorporated byreference. In particular, the skin may be evaluated at the transdermalapplication site for erythema or edema. For example, grades for erythemaand edema may be assigned based on visual observation or palpation:

-   -   Erythema: 0=no visible redness; 1=very slight redness (just        perceptible); 2=slight but defined redness; 3=moderately intense        redness; 4=severe erythema (dark red discoloration of the skin)        5=eschar formation    -   Edema: 0=no visible reactions or swelling; 1=very mild edema        (just perceptible swelling); 2=mild edema (corners of area are        well defined due to swelling); 3=moderate edema (up to 1 mm        swelling); 4=severe edema (more than 1 mm swelling).

The site of application may be evaluated for skin irritation at any timeduring the subject methods. In some instances, the skin is evaluated forirritation while maintaining the transdermal delivery device in contactwith the subject by observing or palpating the skin at regularintervals, e.g., every 0.25 hours, every 0.5 hours, every 1 hour, every2 hours, every 4 hours, every 12 hours, every 24 hours, including every72 hours, or some other interval. For instance, the site of applicationmay be evaluated for skin irritation while maintaining the transdermaldelivery device in contact with the subject, such as 15 minutes afterapplying the transdermal delivery device to the subject, 30 minutesafter applying the transdermal delivery device, 1 hour after applyingthe transdermal delivery device, 2 hours after applying the transdermaldelivery device, 4 hours after applying the transdermal delivery device,8 hours after applying the transdermal delivery device, 12 hours afterapplying the transdermal delivery device, 24 hours after applying thetransdermal delivery device, 48 hours after applying the transdermaldelivery device, 72 hours after applying the transdermal deliverydevice, 76 hours after applying the transdermal delivery device, 80hours after applying the transdermal delivery device, 84 hours afterapplying the transdermal delivery device, 96 hours after applying thetransdermal delivery device, 120 hours after applying the transdermaldelivery device, including 168 hours after applying the transdermaldelivery device.

In other embodiments, the site of transdermal application is evaluatedfor skin irritation after the transdermal delivery device has beenremoved from contact with the subject. For example, the site ofapplication may be evaluated for skin irritation 30 minutes afterremoving the transdermal delivery device, such as 1 hour after removingthe transdermal delivery device, such as 2 hours after removing thetransdermal delivery device, such as 4 hours after removing thetransdermal delivery device, such as 8 hours after removing thetransdermal delivery device, such as 12 hours after removing thetransdermal delivery device, such as 24 hours after removing thetransdermal delivery device, such as 48 hours after removing thetransdermal delivery device, including 72 hours after removing thetransdermal delivery device.

In some embodiments, the site of transdermal application is evaluatedfor skin irritation before the transdermal delivery device is applied toa subject, such as to record the skin color and texture beforecommencing a dosage interval. For example, the site of application maybe evaluated for skin irritation 5 minutes before applying thetransdermal delivery device, such as 10 minutes, such as 30 minutes,such as 60 minutes, such as 120 minutes, such as 240 minutes andincluding 480 minutes before applying the transdermal delivery device.Where methods include multiple dosage intervals applied sequentially,the site of application may be evaluated for skin irritation after eachtransdermal delivery device is removed and before the subsequenttransdermal delivery device is applied. For example, when a firsttransdermal delivery device is removed, the site of application may beevaluated for skin irritation 2 hours, 24 hours and 48 hours afterremoval and before application of a second transdermal delivery device.A subsequent transdermal delivery device may be applied to the previoussite of application immediately after evaluating the skin for irritationor may be applied after a predetermined time after evaluating the skinfor irritation, such as 4 hours, 12 hours, 24 hours, 48 hours, 72 hours,96 hours, 120 hours, 144 hours or 168 hours after evaluating the skinfor irritation.

The site of application may be evaluated for skin irritation one or moretimes before, during or after a dosage interval, such as 2 or moretimes, such as 3 or more times, including 5 or more times before, duringor after a dosage interval. An upper limit for the number of times thesite of application may be evaluated for skin irritation before, duringor after a dosage interval is, in some instances, 10 times or fewer,such as 7 times or fewer, such as 5 times or fewer, such as 3 times orfewer and including 2 times or fewer. In certain embodiments, the numberof times the site of application may be evaluated for skin irritationbefore, during or after a dosage interval ranges such as from 2 times to10 times, such as from 3 times to 9 times, such as from 4 times to 8times and including from 5 times to 7 times. In certain embodiments,skin irritation may be monitored throughout the entire time thetransdermal delivery device is maintained in contact with the subject,such by video monitoring.

Kits

Kits for use in practicing certain methods described herein are alsoprovided. In certain embodiments, the kits include one or moretransdermal delivery devices containing a dexmedetomidine compositionhaving an amount of dexmedetomidine and pressure sensitive adhesive asdescribed above. In certain embodiments, the kits include an adhesiveoverlay as described above. In a given kit that includes two or more ofthe subject transdermal delivery devices, the compositions may beindividually packaged or present within a common container.

In certain embodiments, the kits will further include instructions forpracticing the subject methods or means for obtaining the same (e.g., awebsite URL directing the user to a webpage which provides theinstructions), where these instructions may be printed on a substrate,where substrate may be one or more of: a package insert, the packaging,reagent containers and the like. In the subject kits, the one or morecomponents are present in the same or different containers, as may beconvenient or desirable.

The following examples are offered by way of illustration and not by wayof limitation. Specifically, the following examples are of specificembodiments for carrying out the present invention. The examples are forillustrative purposes only, and are not intended to limit the scope ofthe present invention in any way. Efforts have been made to ensureaccuracy with respect to numbers used (e.g., amounts, temperatures,etc.), but some experimental error and deviation should, of course, beallowed for.

Experimental Materials and Methods Preparation of ExampleDexmedetomidine Transdermal Formulations

Formulations were prepared by mixing dexmedetomidine and a pressuresensitive adhesive in organic solvents (e.g., 30-60 wt % solid contentin ethyl acetate, isopropyl alcohol, hexane, or heptane), followed bymixing. Once a homogeneous mixture was formed, the solution was cast ona release liner (siliconized polyester or fluoropolymer coated polyestersheets of 2-3 mils) and dried at 60°-80° C. for 10-90 minutes. Thesingle layer adhesive films were then laminated to a PET backing, cut tothe desired size, and pouched. In some instances, crosslinkedpolyvinylpyrrolidone (PVP-CLM), polyvinylpyrrolidone K90 (PVP K90),levulinic acid (LA), oleic acid (OA), lauryl lactate (LL), and propyleneglycolmonolaurate (PGML) was added to the adhesive composition.

Transdermal Flux Tests

Human cadaver skin was used and epidermal layers (stratum corneum andviable epidermis) were separated from the full-thickness skin as skinmembrane. Samples were die-cut with an arch punch to a final diameter ofabout 2.0 cm². The release liner was removed and the system was placedon top of the epidermis/stratum corneum with the dexmedetomidineadhesive layer facing the outer surface of the stratum corneum. Gentlepressure was applied to effect good contact between the adhesive layerand stratum corneum. The donor and receptor sides of the Franz cell wereclamped together and the receptor solution containing a phosphate bufferat pH 6.5 and 0.01% gentamicin was added to the Franz cell. The cellswere kept at 32° C.-35° C. for the duration of the experiment. Samplesof the receptor solution were taken at regular intervals and the activeagent concentration was measured by HPLC. The removed receptor solutionwas replaced with fresh solution to maintain sink conditions. The fluxwas calculated from the slope of cumulative amount of the drug permeatedinto the receiver compartment versus time plot.

EXAMPLES Example 1

In-Vitro Flux Obtained from Dexmedetomidine Transdermal CompositionFormulations in PIB/PB Polymers

Pressure-sensitive adhesives used in this example arepolyisobutylene/polybutene (PIB/PB) adhesives. The PIB/PB adhesives aremixtures of high molecular weight PIB (5% Oppanol B100), low molecularweight PIB (25% Oppanol B12) and a polybutene tackifier, e.g., IndopolH1900 or Panalane H-300e (20%) in organic solvent, e.g., heptane (50%).The combination was mixed for about 3 days, until the mixture washomogeneous. Example dexmedetomidine transdermal compositionformulations are shown in Tables 1 and 2.

An in-vitro skin flux study was performed as described above withtransdermal delivery devices having different concentrations ofdexmedetomidine as shown in Table 1. The average dexmedetomidinein-vitro skin flux with respect to time is illustrated in FIG. 1. Asdepicted in FIG. 1, dexemedetomidine in-vitro skin flux was high in theinitial hours in the case of 1% formulation (Formulation 1) as comparedto higher drug loading (Formulations 2 and 3). Formulations 2 and 3 werefound to have needle-like crystals of dexmedetomidine, therefore fluxprofile is constant and did not change with drug loading. However, nocrystals were observed in Formulation 1. Formulation 1 includes asaturated or supersaturated amount of dexmedetomidine.

Dexmedetomidine transdermal formulation was also made using PIB madefrom Indopol H1900 as shown in Table 2. The results of dexmedetomidinein-vitro permeation from 1% dexmedetomidine formulation made with 20%PVP-CLM in PIB/PB adhesive (Formulation 4) through skins that havedifferent skin permeability are illustrated in FIG. 2. FIG. 2(A) showsthe cumulative dexemedetomidine delivered amount with time. The in-vitropermeation of dexmedetomidine deviated depending on the permeability ofthe skin. The in-vitro dexmedetomidine delivered amount could vary from4-35 ug/cm2 at 8 hr. and 15-67 ug/cm2 at 24 hr. FIG. 2(B) shows the fluxor derivative of cumulative drug delivered amount with respect to time.The delivery rate of dexmedetomidine from Formulation 2 reached themaximum at about 5-7 hr, then maintain constant for at least 24 hr. Incase of high permeable skin (Skin#14), the flux might decreased due todepletion. FIG. 2(C) shows the % drug remaining in patch with time. Asdepicted in FIG. 2(C), the utilization of dexmedetomidine obtained fromFormulation 4 was 20-70% after applying the patch for 24 hr.

TABLE 1 % w/w Formulation 1 Formulation 2 Formulation 3 (1% DMT/20% (3%DMT/20% (5% DMT/20% Components CLM/PIB) CLM/PIB) CLM/PIB)Dexmedetomidine 1.00 3.00 5.00 PVP-CLM 20.00 20.00 20.00 PIB/PB(Panalane 79.00 77.00 75.00 H-300e)

TABLE 2 % w/w Formulation 4 Components [1% DMT/20% CLM/PIB(Ind)]Dexmedetomidine 1.00 PVP-CLM 20.00 PIB/PB (Indopol H1900) 79.00

Example 2

In-Vitro Flux Obtained from Dexmedetomidine Transdermal CompositionFormulations in Non-Functionalized Acrylate Polymers

Dexmedetomidine in-vitro flux was measured using non-functionalizedacrylate adhesive. An example of a non-functionalized acrylate adhesiveused experimentally includes non-functionalized acrylate polymerDuro-Tak 87-9301. An in-vitro skin flux study was performed as describedabove with transdermal delivery devices having different concentrationsof dexmedetomidine in non-functional Duro-Tak 87-9301. Dexmedetomidinetransdermal composition formulations are shown in Table 3. The averagedexmedetomidine in-vitro flux with respect to time is illustrated inFIG. 3. As depicted in FIG. 3, higher dexmedetomidine loading gaveincreased in-vitro skin flux.

TABLE 3 % w/w Formula- Formula- Formula- tion 5 tion 6 tion 7 (1% DMT/(2% DMT/ (3% DMT/ Components DT9301) DT9301) DT9301) Dexmedetomidinebase 1.00 2.00 3.00 Pressure Sensitive 99.00 98.00 97.00 AdhesiveDuro-Tak 87-9301

Example 3

In-Vitro Flux Obtained from Dexmedetomidine Transdermal CompositionFormulations in Hydroxyl (—OH) Functionalized Acrylate Polymers

Dexmedetomidine in-vitro flux was measured using hydroxyl (—OH)functionalized acrylate adhesives. Examples of a hydroxyl functionalizedacrylate adhesive used experimentally include hydroxyl functionalizedacrylate polymers, e.g., Duro-Tak 87-4287, Duro-Tak 387/87-2510,Duro-Tak 387/87-2287 and Duro-Tak 387/87-2516. An in-vitro skin fluxstudy was performed as described above with transdermal delivery deviceshaving different concentrations of dexmedetomidine with differenthydroxyl functionalized acrylate adhesives.

Tables 4 and 5 show the dexmedetomidine transdermal compositionformulations with different concentrations of dexmedetomidine inDuro-Tak 87-4287 (acrylate-viny lacetate polymer) or Duro-Tak387/87-2510 (acrylate polymer). The mean dexmedetomidine in-vitro fluxesare illustrated in FIGS. 4 and 5. As depicted in FIGS. 4 and 5,dexmedetomidine in-vitro flux increased with the dexmedetomidine loadingin the formulation.

TABLE 4 % w/w Formula- Formula- Formula- tion 8 tion 9 tion 10 (1% DMT/(2% DMT/ (3% DMT/ Components DT4287) DT4287) DT4287) Dexmedetomidinebase 1.00 2.00 3.00 Pressure Sensitive 99.00 98.00 97.00 AdhesiveDuro-Tak 87-4287

TABLE 5 % w/w Formula- Formula- Formula- tion 11 tion 12 tion 13 (1%DMT/ (2% DMT/ (3% DMT/ Components DT2510) DT2510) DT2510)Dexmedetomidine base 1.00 2.00 3.00 Pressure Sensitive 99.00 98.00 97.00Adhesive Duro-Tak 387/87-2510

Tables 6 show the dexmedetomidine transdermal composition formulationscontaining 1% dexmedetomidine in another hydroxyl functionalizedacrylate polymers containing vinyl acetate, e.g., Duro-Tak 87-2287 (nocrosslinker added polymer) and Duro-Tak 87-2516 (crosslinker addedpolymer). The mean dexmedetomidine in-vitro fluxes are illustrated inFIG. 6. As depicted in FIG. 6, in-vitro flux obtained from Duro-Tak387/87-2287 was slightly higher than that from Duro-Tak 387/87-2516,possibly resulting from the higher adhesion properties of Duro-Tak387/87-2287 compared with Duro-Tak 387/87-2516.

TABLE 6 % w/w Formulation 14 Formulation 15 Components (1% DMT/DT2287)(1% DMT/DT2516) Dexmedetomidine base 1.00 1.00 Pressure SensitiveAdhesive 99.00 0.00 Duro-Tak 387/87-2287 Pressure Sensitive Adhesive0.00 99.00 Duro-Tak 387/87-2516

Example 4

In-Vitro Flux Obtained from 1% Dexmedetomidine Transdermal CompositionFormulations in Non-Functionalized or Hydroxyl (—OH) FunctionalizedAcrylate Polymers

Another set of examples of dexmedetomidine transdermal formulations aretransdermal compositions which include 1% w/w dexmedetomidine withnon-functionalized acrylate polymer (Duro-Tak 87-9301, Formulation 5),hydroxyl functionalized acrylate polymer (Duro-Tak 387/87-2510,Formulation 11) and hydroxyl functionalized acrylate polymer containingvinyl acetate (Duro-Tak 87-4287, Formulation 8). In-vitro fluxexperiments were performed for 3 days and 1 day and the results areshown in FIGS. 7A and 7B, respectively. As depicted in both FIGS. 7A and7B, dexmedetomidine in-vitro flux was less in non-functional adhesivesas compared to hydroxyl functionalized adhesives with the same drugloading.

Example 5

In-Vitro Flux Obtained from Dexmedetomidine Transdermal CompositionFormulations in Acid (—COON) Functionalized or Acid/Hydroxyl (—COOH/OH)Functionalized Acrylate Polymers

Dexmedetomidine in-vitro flux was measured using acid (—COOH)functionalized or acid/hydroxyl (—COOH/OH) functionalized acrylateadhesives. Examples of acid (—COOH) functionalized acrylate adhesiveused in this study is Duro-Tak 387/87-2353 (no crosslinker addedacrylate polymer). The acid/hydroxyl (—COOH/OH) functionalized acrylateadhesive used in this study is Duro-Tak 87-2979 (crosslinker addedacrylate-vinyl acetate polymer).

Tables 7 and 8 show the dexmedetomidine transdermal compositionformulations with different acid (—COOH) functionalized or acid/hydroxyl(—COOH/OH) functionalized acrylate polymers. The concentration ofdexmedetomidine in the formulations was selected based on the solubilityof dexmedetomidine in each adhesive. The solubility of dexmedetomidinein Duro-Tak 387/87-2353 was found to be about 10-15%, whereas that inDuro-Tak 87-2979 was found to be less than 2%. The solubility of drug inacid functionalized acrylate adhesives was greater than that innon-functionalized or hydroxyl functionalized acrylate adhesives.

In-vitro skin flux study was performed as described above. The meandexmedetomidine in-vitro fluxes are illustrated in FIGS. 8 and 9.

TABLE 7 % w/w Formulation 16 Components (14% DMT/DT2353) Dexmedetomidinebase 14.00 Pressure Sensitive Adhesive 86.00 Duro-Tak 387/87-2353

TABLE 8 % w/w Formulation 17 Components (1.5% DMT/DT2979)Dexmedetomidine base 1.00 Pressure Sensitive Adhesive Duro-Tak 87-297999.00

Example 6

In-Vitro Flux Obtained from Dexmedetomidine Transdermal CompositionFormulations in PIB/PB Polymers Containing PVP-CLM and Duro-Tak387/87-2353

Another example of dexmedetomidine transdermal composition formulationis shown in Table 9. In order to increase the solubility of drug inPIB/PB (e.g., Indopol H-1900) adhesive, PVP-CLM and acid (—COOH)functionalized acrylate polymer (Duro-Tak 387/87-2353) were used.Formulations 18 to 21 were prepared with different loadings of Duro-Tak387/87-2353.

As depicted in FIG. 10, Formulations containing acid (—COOH)functionalized acrylate polymer (Duro-Tak 387/87-2353), Formulations 19,20 and 21, appear to have lower initial flux compared with Formulationswithout Duro-Tak 2353 (Formulation 18). The in-vitro flux ofdexmedetomidine did not change with 3% and 6% of acid functionalizedadhesive, however, at 9% acid functionalized adhesive, a slight decreasein the in-vitro flux is observed.

TABLE 9 % w/w Formulation 19 Formulation 20 Formulation 21 Formulation18 (3% DMT/3% DT2353/ (3% DMT/6% DT2353/ (3% DMT/9% DT2353/ Components(3% DMT/20% CLM/PIB) 18.8% CLM/PIB) 18.2% CLM/PIB) 17.6% CLM/PIB)Dexmedetomidine base 3.00 3.00 3.00 3.00 PVP-CLM 20.00 18.8 18.7 18.6Pressure Sensitive Adhesive — 3.00 6.00 9.00 Duro-Tak 387/87-2353 PIB/PB(Indopol H-1900) q.s. to 100 q.s. to 100 q.s. to 100 q.s. to 100

Example 7

In-Vitro Flux Obtained from Dexmedetomidine Transdermal CompositionFormulations in PIB/PB Polymers Containing PVP-CLM and Levulinic Acid

Another example of dexmedetomidine transdermal composition formulationis shown in Table 10. In order to increase the solubility of drug inPIB/PB (e.g., Indopol H-1900) adhesive in presence of 20% PVP-CLM,various concentrations of an acid were used to test increaseddexmedetomidine solubility. Formulations 22 to 25 were prepared withdifferent loadings of levulinic acid.

TABLE 10 % w/w Formulation 22 Formulation 23 Formulation 24Formulation25 (3% DMT/0.6% LA/ (3% DMT/0.9% LA/ (3% DMT/1.75% LA/ (3%DMT/6.9% LA/ Components 20% CLM/PIB) 20% CLM/PIB) 20% CLM/PIB) 20%CLM/PIB) Dexmedetomidine base 3.00 3.00 3.00 3.00 PVP-CLM 20.00 20.0020.00 20.00 Levulinic Acid 0.60 0.90 1.75 6.90 PIB/PB (Indopol H-1900)q.s. to 100 q.s. to 100 q.s. to 100 q.s. to 100

As depicted in FIG. 10, in-vitro flux of dexmedetomidine was reduceddramatically where the formulation included 6.9% of levulinic acid.However, at a concentration of 1.75% levulinic acid, in-vitro flux wascomparable to lower concentrations of levulinic acid (i.e., 0.6% and0.9%). The initial flux obtained from formulations containing levulenicacid (Formulations 22,23,24 and 25) was lower than that from formulationwithout levulinic acid (Formulation 18) However, after 24 hr, the fluxobtained from the formulations containing levulenic acid (Formulations22,23,24 and 25) appear to be higher than that from formulation withoutlevulinic acid (Formulation 17). Dexmedetomidine crystals were observedat levulinic acid concentrations of 1.75% and lower.

Example 8

In-Vitro Flux Obtained from Dexmedetomidine Transdermal CompositionFormulations in PIB/PB Polymers Containing PVP-CLM and Lauryl Lactate orPropylene Glycolmonolaurate

Another example of dexmedetomidine transdermal composition formulationsare shown in Tables 11 and 12. Dexmedetomidine has solubility of 5 to10% in lauryl lactate and propylene glycolmonolaurate. Each of lauryllactate and propylene glycolmonolaurate increase solubility ofdexmedetomidine in the PIB/PB adhesive in the subject formulations.In-vitro flux profiles of Formulations 26 to 28 are shown in FIG. 12.In-vitro flux profiles of Formulations 29 to 31 are shown in FIG. 13.Formulations 26 to 31 were found to have needle-like crystals ofdexmedetomidine,

TABLE 11 % w/w Formula- Formula- Formula- tion 26 tion 27 tion 28 (3%DMT/ (3% DMT/ (3% DMT/ 3% LL/20% 6% LL/20% 9% LL/20% Components CLM/PIB)CLM/PIB) CLM/PIB) Dexmedetomidine base 3.00 3.00 3.00 PVP-CLM 20.0020.00 20.00 Lauryl lactate 3.0 6.0 9.0 PIB/PB (Indopol q.s. q.s. q.s.H-1900) to 100 to 100 to 100

TABLE 12 % w/w Formulation29 Formulation30 Formulation31 (3% DMT/4%PGML/ (3% DMT/8% PGML/ (3% DMT/12% PGML/ Components 20% CLM/PIB) 20%CLM/PIB) 20% CLM/PIB) Dexmedetomidine base 3.00 3.00 3.00 PVP-CLM 20.0020.00 20.00 Propylene glycolmonolaurate 4.0 8.0 12.0 PIB/PB (IndopolH-1900) q.s. to 100 q.s. to 100 q.s. to 100

Example 9

In-Vitro Flux Obtained from Dexmedetomidine Transdermal CompositionFormulations in Duro-Tak 387/87-2287 Polymers Containing Levulinic Acid,PVP K90 or Duro-Tak 387/87-2353

Another set of examples of dexmedetomidine transdermal formulationinclude transdermal compositions having 1% w/w dexmedetomidine with asolubilizer to improve physical stability of the composition. In theseformulations, levulinic acid, PVP K90 and Duro-Tak 87-2353 wereemployed. The formulation compositions are shown in Tables 13, 14 and15. In-vitro flux profiles for transdermal compositions having 1%dexmedetomidine with 0.3% and 0.6% levulinic acid are shown in FIG.14(A). In-vitro flux profiles for transdermal compositions having 1%dexmedetomidine with 5% and 10% PVP K90 are shown in FIG. 14(B).In-vitro flux profiles for transdermal compositions having 1%dexmedetomidine with 2% or 3% Duro-Tak 387/87-2353 are shown in FIG.14(C). From the in-vitro flux profiles, levulinic acid enhanced thepermeation after application for 15 hr., PVP K90 delayed transdermalflux of dexmedetomidine whereas Duro-Tak 2353 slightly reducedtransdermal flux.

TABLE 13 % w/w Formulation 32 Formulation 33 (1% DMT/0.3% LA/ (1%DMT/0.6% LA/ Components DT2287) DT2287) Dexmedetomidine base 1.00 1.00Levulinic acid 0.30 0.60 Pressure Sensitive 98.70 98.40 AdhesiveDuro-Tak 387/ 87-2287

TABLE 14 % w/w Formulation 34 Formulation 35 (1% DMT/5% PVP- (1% DMT/10%PVP- Components K90/DT2287) K90/DT2287) Dexmedetomidine base 1.00 1.00PVP K90 5.00 10.00 Pressure Sensitive Adhesive 94.00 89.00 Duro-Tak387/87-2287

TABLE 15 % w/w Formulation 36 Formulation 37 (1% DMT/2% (1% DMT/3%Components DT2353/DT2287) DT2353/DT2287) Dexmedetomidine 1.00 1.00 basePressure Sensitive 2.00 3.00 Adhesive Duro-Tak 387/87-2353 PressureSensitive 97.00 96.00 Adhesive Duro-Tak 387/87-2287

Example 10

In-Vitro Flux Obtained from Dexmedetomidine Transdermal CompositionFormulations in Duro-Tak 87-9301 Polymers Containing Levulinic Acid,Oleic Acid or Duro-Tak 387/87-2353

Another set of examples of dexmedetomidine transdermal formulationinclude transdermal compositions having 3% w/w dexmedetomidine andnon-functionalized acrylate polymer Duro-Tak 87-9301 in combination with3.3% levulinic acid, 5% Oleic acid or 15% Duro-Tak 387/87-2353. Theformulation compositions are shown in Table 16. In-vitro flux profilesfor these formulations (Formulations 38,39 and 40), compared with 3%dexmedetomidine in non-functionalized acrylate polymer Duro-Tak 87-9301without additive (Formulation 7) are illustrated in FIG. 15.Compositions having just 3% dexmedetomidine and non-functionalizedacrylate polymer Duro-Tak 87-9301 were supersaturated. Levulinic acidand oleic acid were used as a solubilizer and permeation enhancer andincreased flux at the beginning of in-vitro flux, but declined withtime. Like with the 1% dexmedetomidine compositions, Duro-Tak 87-2353reduced flux.

TABLE 16 % w/w Formulation 38 Formulation 39 Formulation 40 (3% DMT/3.3%(3% DMT/5% OA/ (3% DMT/15% Components LA/DT9301) DT9301) DT2353/DT9301)Dexmedetomidine base 3.00 3.00 3.00 Levulinic acid 3.30 0.00 0.00 Oleicacid 0.00 5.00 0.00 Pressure Sensitive 0.00 0.00 15.00 Adhesive Duro-Tak387/87-2353 Pressure Sensitive 93.70 92.00 82.00 Adhesive Duro-Tak87-9301

Example 11

In-Vitro Permeation of Dexmedetomidine Obtained from 1%, 2%, 3% and 4%Dexmedetomidine in the Mixture of Adhesives (15% Duro-Tak2353 inDuro-Tak 2287)

Dexmedetomidine transdermal composition formulations containing themixture of hydroxyl functionalized acrylate polymer (e.g., Duro-Tak87-2287) and acid functionalized acrylate polymer (e.g., Duro-Tak87-2353) are summarized in Table 17. Formulations 41 to 44 were preparedwith different loadings of dexmedetomidine.

TABLE 17 % w/w Formulation 41 Formulation 42 Formulation 43 Formulation44 (1% DMT/15% (2% DMT/15% 3% DMT/15% 4% DMT/15% ComponentsDT2353/DT2287) DT2353/DT2287 DT2353/DT2287 DT2353/DT2287 Dexmedetomidinebase 1.00 2.00 3.00 4.00 Pressure Sensitive 15.00 15.00 15.00 15.00Adhesive Duro-Tak 2353 Pressure Sensitive 84.00 83.00 82.00 81.00Adhesive Duro-Tak 2287

As depicted in FIG. 16, in-vitro flux of dexmedetomidine increased withincreasing percent of dexmedetomidine loading.

Example 12

In-Vitro Permeation of Dexmedetomidine Obtained from DexmedetomidineFormulations Containing Oleic Acid

Another example of dexmedetomidine transdermal composition formulationsis summarized in Table 18. In order to increase the solubility ofdexmedetomidine in the hydroxyl functionalized acrylate polymer (e.g.,Duro-Tak 87-2287), oleic acid was used. Formulations 45 to 47 wereprepared with different loadings of oleic acid and dexmedetomidine.

TABLE 18 % w/w Formulation 45 Formulation 46 Formulation 47 (3% DMT/5%OA/ 3% DMT/7% OA/ 3% DMT/5% OA/ Components DT2287 DT2287 DT2287Dexmedetomidine 3.00 3.00 4.00 base Oleic acid 5.00 7.00 5.00 PressureSensitive 92.00 90.00 91.00 Adhesive Duro-Tak 2287

As depicted in FIG. 17, dexmedetomidine in formulations containing oleicacid has a higher flux than a dexmedetomidine composition (e.g.,Formulation 43) which does not contain oleic acid. Oleic acid enhancedthe permeation of dexmedetomidine through the skin. An increase of oleicacid from 5% to 7% (e.g. Formulation 46) did not show an enhancementeffect as compared to the formulation containing 5% oleic acid (e.g.Formulation 45). This may be the result of the contribution of oleicacid in increasing in solubility of dexmedetomidine in the composition.A comparison of Formulation 45 and Formulation 47 shows that thein-vitro flux increases with increasing percent drug loading.

Example 13

In-Vitro Permeation of Dexmedetomidine Obtained from DexmedetomidineFormulations Containing Levulinic Acid

Dexmedetomidine transdermal formulations were also prepared withlevulinic acid. The composition is shown in Table 19.

TABLE 19 % w/w Formulation 48 Formulation 49 (3% DMT/4% (4% DMT/4%Components LA/DT2287) LA/DT2287) Dexmedetomidine base 3.00 4.00Levulinic acid 4.00 4.00 Pressure Sensitive 93.00 92.00 AdhesiveDuro-Tak 2287

As shown in FIG. 18, in-vitro flux of dexmedetomidine in formulationscontaining levulinic acid (Formulations 48 and 49) increased withpercent dexmedetomidine loading. The enhancement effect of levulinicacid on permeation of dexmedetomidine through the skin was higher thanoleic acid.

The results of percent in-vitro penetration of dexmedetomidine informulations 43, 45 and 48 relative to the amount of dexmedetomidine inthe patch are summarized in Table 20. Formulations 45 and 48, whichcontain levulinic acid and oleic acid, demonstrate a substantialenhancement in permeation of dexmedetomidine under in-vitro condition.

TABLE 20 % Permeation of dexmedetomidine Amount of base relative to theFormulation Formulation dexmedetomidine amount of drug in No. of No.names base in patch (μg) patch after 7 days replicates Formulation 3%DMT/15% 690 ± 27 18 ± 4 4 43 DT2353/DT2287 Formulation 3% DMT/5% Oleic486 ± 11 52 ± 4 4 45 acid/DT2287 Formulation 3% DMT/4% Levulinic 573 ±39 74 ± 5 5 48 acid/DT2287

The solubility of dexmedetomidine in hydroxyl functionalized acrylatepolymer was less than 1%. In order to increase the dexmedetomidine, anacid functionalized acrylate polymer (e.g., Duro-Tak2353), oleic acidand levulinic acid were used. The solubility of dexmedetomidine inDuro-Tak2353, oleic acid and levulinic acid was about 10-15%, 40% and60% respectively. The amount of acid added in the formulation wasadjusted according to the solubility of each component in theformulation.

After preparation, the crystal presence was examined using microscope.Results obtained from this microscope examination indicated that allformulations (Formulations 41 to 48) did not contain crystals.

Example 14

In-Vitro Flux Obtained from Different Backings

Pressure-sensitive adhesives used in this example arepolyisobutylene/polybutene (PIB/PB) adhesives. The PIB/PB adhesives aremixtures of high molecular weight PIB (5% Oppanol B100), low molecularweight PIB (25% Oppanol B12) and a polybutene tackifier, e.g., IndopolH1900 or Panalane H-300e (20%), in an organic solvent, e.g., heptane(50%). The combination was mixed for about 3 days, until the mixture washomogeneous. Example dexmedetomidine transdermal compositionformulations are shown in Table 21. Same formulation was coated onrelease liner but laminated with three different backing materials:backing 1 has a MVTR value (g/m²/24 hr) around 10, Backing 2 has a MVTRvalue around 50 (g/m²/24 hr), and backing 3 has MVTR value around150(g/m²/24 hr).

The average dexmedetomidine in-vitro skin flux with respect to time isillustrated in FIG. 19. As depicted in FIG. 19, dexmedetomidine in-vitroskin flux was similar for backing 1 and 2. But it is significantly lowerwith backing 3.

TABLE 21 Components % w/w Dexmedetomidine 1.00 PVP-CLM 20.00 PIB/PB(Indopol H1900) 79.00

Example 15

In-Vitro Flux Obtained from Formulations with Lauryl Lactate as Enhancer

Another set of examples of dexmedetomidine transdermal formulationinclude transdermal compositions having 2-4% w/w dexmedetomidine with anenhancer to improve skin permeability. In these formulations, lauryllactate (LL) and Duro-Tak 87-2287 were employed. The formulationcompositions are shown in Table 22. In-vitro flux profiles fortransdermal compositions. FIGS. 20 and 21 show the flux on two differentskin samples. From the in-vitro flux profiles, LL shows its skinpermeability enhancement effect. The flux is also proportional to APIloading.

TABLE 22 % w/w Dexmedetomidine base Components 2 2 3 4 Lauryl lactate 05 5 5 Pressure Sensitive 98 93 92 91 Adhesive Duro-Tak 87-2287

The flux profile of all formulations (Formulations 41 to 48) showed aclear increasing trend in flux with time during the first 24 hours(FIGS. 16 to 18). This is followed by a gradual decrease in flux withtime. As such, the increase in flux during the first 24 hours may, incertain instances, be useful for achieving a rapid higher initialtherapeutic concentration in the body. Where there is a decrease in fluxwith time, the decrease in flux could be due to the crystallization ofthe drug in the adhesive induced by the absorbed water in the patch.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

1. A method of treating attention deficit hyperactivity disorder (ADHD),anxiety or insomnia in a subject, the method comprising: applying to askin surface of a subject diagnosed as having ADHD, anxiety or insomniaa transdermal delivery device comprising: a dexmedetomidine composition,wherein the dexmedetomidine composition comprises: dexmedetomidine; anda pressure sensitive adhesive; and a backing layer; in a mannersufficient to deliver dexmedetomidine to the subject to treat ADHD inthe subject.
 2. The method according to claim 1, wherein the subject isdiagnosed as having ADHD.
 3. The method according to claim 1, whereinthe subject is diagnosed as having anxiety.
 4. The method according toclaim 1, wherein the subject is diagnosed as having insomnia.
 5. Themethod according to claim 1, wherein the method comprises maintainingthe transdermal delivery device in contact with the subject for aduration from 4 hours to 24 hours. 6-7. (canceled)
 8. The methodaccording to claim 1, wherein the subject is a child under the age of 8.9. The method according to claim 1, wherein the subject is a child underthe age of
 5. 10. The method according to claim 1, wherein thetransdermal delivery device is configured to reach a peak rate ofdexmedetomidine delivery at about 30 minutes after applying thetransdermal delivery device to the subject.
 11. The method according toclaim 1, wherein the transdermal delivery device is configured to reacha peak rate of dexmedetomidine delivery at about 3 hours after applyingthe transdermal delivery device to the subject.
 12. The method accordingto claim 1, wherein the transdermal delivery device is configured todeliver dexmedetomidine to the subject at a rate ranging from 20 μg/12hours to 100 μg/12 hours.
 13. The method according to claim 1, whereinthe transdermal delivery device is configured to deliver dexmedetomidineto the subject in a manner sufficient to maintain a mean plasmaconcentration of dexmedetomidine in the subject of from about 0.01 ng/mLto about 0.4 ng/mL.
 14. The method according to claim 13, wherein thetransdermal delivery device is configured to deliver dexmedetomidine tothe subject in a manner sufficient to achieve a peak plasmaconcentration of dexmedetomidine in the subject at about 1 hour afterapplying the transdermal delivery device to the subject.
 15. The methodaccording to claim 13, wherein the transdermal delivery device isconfigured to deliver dexmedetomidine to the subject in a mannersufficient to achieve a peak plasma concentration of dexmedetomidine inthe subject at about 2 hours after applying the transdermal deliverydevice to the subject.
 16. The method according to claim 13, wherein thetransdermal delivery device is configured to deliver dexmedetomidine tothe subject in a manner sufficient to achieve a peak plasmaconcentration of dexmedetomidine in the subject at about 3 hours afterapplying the transdermal delivery device to the subject.
 17. The methodaccording to claim 1, wherein the pressure sensitive adhesive comprisesa vinyl polymer. 18-32. (canceled)
 33. The method according to claim 1,wherein the pressure sensitive adhesive comprises crosslinkedpolyvinylpyrrolidone or crosslinked polyacrylic acid or a combinationthereof.
 34. The method according to claim 1, wherein thedexmedetomidine composition consists of dexmedetomidine and the pressuresensitive adhesive.
 35. The method according to claim 1, wherein thetransdermal delivery device comprises a single layer matrix comprisingthe dexmedetomidine composition. 36-73. (canceled)